Drug Information

Drug (ID: DG00069) and It's Reported Resistant Information

• Name: Fluorouracil
• Synonyms: 5-Fluorouracil; 51-21-8; fluorouracil; 5-FU; Fluoroplex; Adrucil; Efudex; Carac; Fluracil; Fluoroblastin; 5-fluoropyrimidine-2,4(1H,3H)-dione; Kecimeton; Timazin; Carzonal; Efudix; Arumel; Fluril; Queroplex; Fluracilum; Ulup; 5-Fluoracil; Phthoruracil; Fluro Uracil; 5-Fluoro-2,4(1H,3H)-pyrimidinedione; Ftoruracil; Fluorouracilum; Efurix; Fluri; 5 Fluorouracil; Effluderm (free base); 5-fluoro-1H-pyrimidine-2,4-dione; Fluorouracilo; Fluroblastin; Phtoruracil; 2,4-Dihydroxy-5-fluoropyrimidine; 2,4(1H,3H)-Pyrimidinedione, 5-fluoro-; Adrucil; Effluderm; Fluorouracile; Fluoruracil; Fluracedyl; Flurodex; Neofluor; Onkofluor; Ribofluor; Tetratogen; URF; Allergan Brand of Fluorouracil; Biosyn Brand of Fluorouracil; CSP Brand of Fluorouracil; Cinco FU; Dakota Brand of Fluorouracil; Dermatech Brand of Fluorouracil; Dermik Brandof Fluorouracil; Ferrer Brand of Fluorouracil; Fluoro Uracile ICN; Fluorouracil GRY; Fluorouracil Mononitrate; Fluorouracil Monopotassium Salt; Fluorouracil Monosodium Salt; Fluorouracil Potassium Salt; Fluorouracil Teva Brand; Fluorouracile Dakota; Fluorouracile [DCIT]; Fluorouracilo Ferrer Far; Gry Brand of Fluorouracil; Haemato Brand of Fluorouracil; Haemato fu; Hexal Brand of Fluorouracil; ICN Brand of Fluorouracil; Inhibits thymilidate synthetase; Medac Brand of Fluorouracil; Neocorp Brand of Fluorouracil; Onkoworks Brand of Fluorouracil; Ribosepharm Brand of Fluorouracil; Riemser Brand of Fluorouracil; Roche Brand of Fluorouracil; Teva Brand of Fluorouracil; F 6627; F0151; IN1335; U 8953; Adrucil (TN); Carac (TN); Dakota, Fluorouracile; Efudex (TN); Fluoro-Uracile ICN; Fluoro-uracile; Fluoro-uracilo; Fluoroplex (TN); Fluorouracil-GRY; Fluorouracilo [INN-Spanish]; Fluorouracilum [INN-Latin]; Haemato-fu; Ro 2-9757; U-8953; Ro-2-9757; Fluorouracil (JP15/USP/INN); Fluorouracil [USAN:INN:BAN:JAN]; 1-fluoro-1h-pyrimidine-2,4-dione; 2,4-Dioxo-5-fluoropryimidine; 2,4-Dioxo-5-fluoropyrimidine; 5 FU Lederle; 5 FU medac; 5 Fluorouracil biosyn; 5 HU Hexal; 5-FU (TN); 5-FU Lederle; 5-FU medac; 5-Faracil; 5-Fluor-2,4(1H,3H)-pyrimidindion; 5-Fluor-2,4(1H,3H)-pyrimidindion [Czech]; 5-Fluor-2,4-dihydroxypyrimidin; 5-Fluor-2,4-dihydroxypyrimidin [Czech]; 5-Fluor-2,4-pyrimidindiol; 5-Fluor-2,4-pyrimidindiol [Czech]; 5-Fluoracil [German]; 5-Fluoracyl; 5-Fluoro-2,4-pyrimidinedione; 5-Fluoropyrimidin-2,4-diol; 5-Fluoropyrimidine-2,4-dione; 5-Fluorouracil-biosyn; 5-Fluoruracil; 5-Fluoruracil [German]; 5-Ftouracyl; 5-HU Hexal; 5-fluoro uracil; 5FU
• Indication:
  In total 2 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1], [2]
  Colorectal cancer [ICD-11: 2B91]; Investigative; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (11 diseases)
  Breast cancer [ICD-11: 2C60]; [3]
  Colon cancer [ICD-11: 2B90]; [4]
  Colorectal cancer [ICD-11: 2B91]; [5]
  Colorectal peritoneal carcinomatosis [ICD-11: 2D91]; [6]
  Esophageal cancer [ICD-11: 2B70]; [7]
  Gastric cancer [ICD-11: 2B72]; [8]
  Kidney cancer [ICD-11: 2C90]; [9]
  Liver cancer [ICD-11: 2C12]; [10]
  Metastatic colorectal cancer [ICD-11: 2D85]; [11]
  Neuroendocrine carcinoma [ICD-11: 2D4Y]; [12]
  Pancreatic cancer [ICD-11: 2C10]; [13]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (10 diseases)
  Breast cancer [ICD-11: 2C60]; [14]
  Colon cancer [ICD-11: 2B90]; [15]
  Colorectal cancer [ICD-11: 2B91]; [1], [2]
  Esophageal cancer [ICD-11: 2B70]; [16]
  Gastric cancer [ICD-11: 2B72]; [17]
  Liver cancer [ICD-11: 2C12]; [18]
  Lung cancer [ICD-11: 2C25]; [19]
  Oral squamous cell carcinoma [ICD-11: 2B6E]; [20]
  Pancreatic cancer [ICD-11: 2C10]; [21]
  Salivary gland carcinoma [ICD-11: 2E60]; [22]
• Target: Candida Thymidylate synthase (Candi TMP1); TYSY_CANAL; [1]
• Target: Dihydrothymine dehydrogenase (DPYD); DPYD_HUMAN; [1]
• Target: TERT messenger RNA (TERT mRNA); TERT_HUMAN; [1]
• Target: Thymidylate synthase messenger RNA (TYMS mRNA); TYSY_HUMAN; [1]
• Formula: C4H3FN2O2
• IsoSMILES: C1=C(C(=O)NC(=O)N1)F
• InChI: 1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)
• InChIKey: GHASVSINZRGABV-UHFFFAOYSA-N
• PubChem CID: 3385
• ChEBI ID: CHEBI:46345
• TTD Drug ID: D05LEO
• VARIDT ID: DR00153
• INTEDE ID: DR0020
• DrugBank ID: DB00544

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-138 [23]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [23]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Leukemia [ICD-11: 2B33.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HL60 cells; Peripheral blood; Homo sapiens (Human); CVCL_0002
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-138 was found up-regulated in the vincristine-induced multidrug resistance (MDR) leukemia cell line HL-60/VCR as compared with HL-60 cells. Up-regulation of miR-138 could reverse resistance of both P-glycoprotein-related and P-glycoprotein-non-related drugs on HL-60/VCR cells, and promote adriamycin-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of adriamycin.

Osteosarcoma [ICD-11: 2B51]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-140 [24]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone deacetylase 4 (HDAC4) [24]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Osteosarcoma [ICD-11: 2B51.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Nasopharyngeal cancer [ICD-11: 2B6B]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-3188 [25]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: C666-1 cells; Throat; Homo sapiens (Human); CVCL_7949
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3k/AkT-c-JUN.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [25]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Nasopharyngeal carcinoma [ICD-11: 2B6B.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: HNE1 cells; Nasopharynx; Homo sapiens (Human); CVCL_0308
• In Vitro Model: 5-8F cells; Nasopharynx; Homo sapiens (Human); CVCL_C528
• In Vitro Model: CNE2 cells; Nasopharynx; Homo sapiens (Human); CVCL_6889
• In Vitro Model: C666-1 cells; Throat; Homo sapiens (Human); CVCL_7949
• In Vitro Model: CNE1 cells; Throat; Homo sapiens (Human); CVCL_6888
• In Vitro Model: HONE1 cells; Throat; Homo sapiens (Human); CVCL_8706
• In Vitro Model: 6-10B cells; Nasopharynx; Homo sapiens (Human); CVCL_C529
• In Vitro Model: SUNE-1 cells; Nasopharynx; Homo sapiens (Human); CVCL_6946
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3k/AkT-c-JUN.

Oral squamous cell carcinoma [ICD-11: 2B6E]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-654-5p [20]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR654-5p targets GRAP to promote proliferation, metastasis, and chemoresistance of oral squamous cell carcinoma through Ras/MAPk signaling.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GRB2-related adapter protein (GRAP) [20]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: Tca8113 cells; Tongue; Homo sapiens (Human); CVCL_6851
• In Vitro Model: CAL-27 cells; Tongue; Homo sapiens (Human); CVCL_1107
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR654-5p targets GRAP to promote proliferation, metastasis, and chemoresistance of oral squamous cell carcinoma through Ras/MAPk signaling.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-365a-3p [26]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta5-integrin/c-Met signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: C9-IV3 cells; Oral; Homo sapiens (Human); N.A.
• In Vitro Model: CGHNC9 cells; Oral; Homo sapiens (Human); N.A.
• In Vitro Model: OC-3 cells; Oral; Homo sapiens (Human); CVCL_WL09
• In Vivo Model: CB17-SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-365-3p targets EHF to inhibit OSCC migration, invasion, and metastasis through kRT16.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: ETS homologous factor (EHF) [26]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta5-integrin/c-Met signaling pathway; Inhibition; hsa01521
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: C9-IV3 cells; Oral; Homo sapiens (Human); N.A.
• In Vitro Model: CGHNC9 cells; Oral; Homo sapiens (Human); N.A.
• In Vitro Model: OC-3 cells; Oral; Homo sapiens (Human); CVCL_WL09
• In Vivo Model: CB17-SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-365-3p targets EHF to inhibit OSCC migration, invasion, and metastasis through kRT16.

Esophageal cancer [ICD-11: 2B70]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-141-3p [27]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: EC9706-R cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: Het-1A cells; Esophagus; Homo sapiens (Human); CVCL_3702
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis Detection assay
• Mechanism Description: Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via down-regulation of PTEN.

Key Molecule: hsa-mir-221 [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin/EMT signaling pathway; Activation; hsa04310
• In Vitro Model: OE19 cells; Esophagus; Homo sapiens (Human); CVCL_1622
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) staining assay
• Mechanism Description: miR-221 mediates chemoresistance of esophageal adenocarcinoma by direct targeting and reducing of Dkk2 expression.

Key Molecule: hsa-miR-193a-3p [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: KYSE510 cells; Esophagus; Homo sapiens (Human); CVCL_1354
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-193a-3p increased the radioresistance and chemoresistance of oesophageal squamous cell carcinoma (ESCC) cells. In contrast, the down-regulation of miR-193a-3p decreased the radioresistance and chemoresistance of ESCC cells. In addition, miR-193a-3p inducing DNA damage has also been demonstrated through measuring the level of gamma-H2AX associated with miR-193a-3p. Moreover, a small interfering RNA(siRNA)-induced repression of the PSEN1 gene had an effect similar to that of miR-193a-3p up-regulation. The above processes also inhibited oesophageal cancer cells apoptosis. These findings suggest that miR-193a-3p contributes to the radiation and chemotherapy resistance of oesophageal carcinoma by down-regulating PSEN1.

Key Molecule: hsa-miR-193a-3p [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: KYSE510 cells; Esophagus; Homo sapiens (Human); CVCL_1354
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-193a-3p increased the radioresistance and chemoresistance of oesophageal squamous cell carcinoma (ESCC) cells. The regulation role of miR-193a-3p on multi-chemoresistance and radioresistance were mediated by PSEN1.

Key Molecule: hsa-miR-193a-3p [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: KYSE510 cells; Esophagus; Homo sapiens (Human); CVCL_1354
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-193a-3p increased the radioresistance and chemoresistance of oesophageal squamous cell carcinoma (ESCC) cells. The regulation role of miR-193a-3p on multi-chemoresistance and radioresistance were mediated by PSEN1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [27]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: EC9706-R cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: Het-1A cells; Esophagus; Homo sapiens (Human); CVCL_3702
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis Detection assay
• Mechanism Description: Involvement of microRNA-141-3p in 5-fluorouracil and oxaliplatin chemo-resistance in esophageal cancer cells via down-regulation of PTEN.

Key Molecule: Dickkopf-related protein 2 (DKK2) [7]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin/EMT signaling pathway; Activation; hsa04310
• In Vitro Model: OE19 cells; Esophagus; Homo sapiens (Human); CVCL_1622
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) staining assay
• Mechanism Description: miR-221 mediates chemoresistance of esophageal adenocarcinoma by direct targeting and reducing of Dkk2 expression.

Key Molecule: Presenilin-1 (PSEN1) [16]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: KYSE510 cells; Esophagus; Homo sapiens (Human); CVCL_1354
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-193a-3p increased the radioresistance and chemoresistance of oesophageal squamous cell carcinoma (ESCC) cells. In contrast, the down-regulation of miR-193a-3p decreased the radioresistance and chemoresistance of ESCC cells. In addition, miR-193a-3p inducing DNA damage has also been demonstrated through measuring the level of gamma-H2AX associated with miR-193a-3p. Moreover, a small interfering RNA(siRNA)-induced repression of the PSEN1 gene had an effect similar to that of miR-193a-3p up-regulation. The above processes also inhibited oesophageal cancer cells apoptosis. These findings suggest that miR-193a-3p contributes to the radiation and chemotherapy resistance of oesophageal carcinoma by down-regulating PSEN1.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-130a-3p [28]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-130a-3p downregulation on enhancement of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the increase of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: hsa-miR-130a-3p [28]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-130a-3p upregulation on suppression of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the inhibition of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: hsa-miR-148a-3p [28]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-148a-3p downregulation on enhancement of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the increase of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: hsa-miR-148a-3p [28]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: KYSE-270 cells; Esophagus; Homo sapiens (Human); CVCL_1350
• In Vitro Model: KYSE-410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The effect of miR-148a-3p upregulation on suppression of protein levels was more pronounced for Bcl-2 compared to XIAP, whereas the inhibition of miR-130a-3p resulted in a more pronounced increase of protein levels of XIAP compared to Bcl-2. Both, up- and downregulation of miR-130a-3p and miR-148a-3p increased sensitivity towards chemotherapy in ESCC and complex role of miR-130a-3p and miR-148a-3p balance on drug resistance and tumor biology in esophageal squamous cell carcinoma.

Key Molecule: Long non-protein coding RNA 261 (LINC00261) [29]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: TE-5 cells; Esophageal; Homo sapiens (Human); CVCL_1764
• In Vivo Model: BALB/c nude mouse xenograft mode; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.

Key Molecule: hsa-mir-224 [30]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: DESC1/EGFR/AKT signaling pathway; Regulation; hsa04012
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUSC7 suppressed the proliferation and chemotherapy resistance of ESCC cells by increasing DESC1 expression via inhibiting miR-224.

Key Molecule: Tumor suppressor candidate 7 (TUSC7) [30]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: DESC1/EGFR/AKT signaling pathway; Regulation; hsa04012
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUSC7 suppressed the proliferation and chemotherapy resistance of ESCC cells by increasing DESC1 expression via inhibiting miR-224.

Key Molecule: hsa-mir-200c [31]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Endoscopy; Computed tomography assay; Positron emission tomography assay
• Mechanism Description: Serum miR-200c levels are useful for predicting the response to chemotherapy (cisplatin, 5-fluorouracil, and Adriamycin (ACF) or cisplatin, 5-fluorouracil, and docetaxel (DCF) ) in patients with esophageal cancer who underwent preoperative chemotherapy followed by surgery.

Key Molecule: hsa-mir-148a [32]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-148a sensitized chemotherapy-sensitive oesophageal cancer cell lines to cisplatin and, to a lesser extent, to 5-flurouracil and attenuated resistance in chemotherapy-resistant variants.

Key Molecule: hsa-mir-148a [32]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: kYSE410 cells; Esophagus; Homo sapiens (Human); CVCL_1352
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-148a sensitized chemotherapy-sensitive oesophageal cancer cell lines to cisplatin and, to a lesser extent, to 5-flurouracil and attenuated resistance in chemotherapy-resistant variants.

Key Molecule: hsa-mir-296 [33]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Down-regulation of miR-296 could confer sensitivity of both P-glycoprotein-related and P-glycoprotein-nonrelated drugs on esophageal cancer cells, and might promote ADR-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of ADR. Down-regulation of miR-296 could significantly decrease the expression of P-glycoprotein, Bcl-2, and the transcription of MDR1, but up-regulate the expression of Bax.

Key Molecule: hsa-mir-27a [34]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulation of miR-27a significantly decreased expression of MDR1, but did not alter the expression of MRP, miR-27a could possibly mediate drug resistance, at least in part through regulation of MDR1 and apoptosis.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [33], [34]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Down-regulation of miR-296 could confer sensitivity of both P-glycoprotein-related and P-glycoprotein-nonrelated drugs on esophageal cancer cells, and might promote ADR-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of ADR. Down-regulation of miR-296 could significantly decrease the expression of P-glycoprotein, Bcl-2, and the transcription of MDR1, but up-regulate the expression of Bax. And down-regulation of miR-27a significantly decreased expression of MDR1, but did not alter the expression of MRP, miR-27a could possibly mediate drug resistance, at least in part through regulation of MDR1 and apoptosis.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydropyrimidine dehydrogenase [NADP(+)] [29]

• Molecule Alteration: Methylation; Down-regulation
• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• In Vitro Model: TE-5 cells; Esophageal; Homo sapiens (Human); CVCL_1764
• In Vivo Model: BALB/c nude mouse xenograft mode; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer.

Key Molecule: Transmembrane protease serine 11E (TM11E) [30]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: DESC1/EGFR/AKT signaling pathway; Regulation; hsa04012
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUSC7 suppressed the proliferation and chemotherapy resistance of ESCC cells by increasing DESC1 expression via inhibiting miR-224.

Gastric cancer [ICD-11: 2B72]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Pvt1 oncogene (PVT1) [35]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nod/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA PVT1 can inhibit apoptosis and enhance the 5-Fu resistance via Increasing Bcl2 expression in Gastric Cancer.

Key Molecule: Long non-protein coding RNA (XLOC_006753) [36]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA XLOC_006753 promotes the development of multidrug resistance in gastric cancer cells through the PI3k/Akt/mTOR signaling pathway.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [8]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: RT-PCR; Luciferase reporter assay; Pull down assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MALAT1 acts as a competing endogenous RNA for miR23b-3p and attenuates the inhibitory effect of miR23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells.

Key Molecule: hsa-miR-23b-3p [8]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: RT-PCR; Luciferase reporter assay; Pull down assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MALAT1 acts as a competing endogenous RNA for miR23b-3p and attenuates the inhibitory effect of miR23b-3p on ATG12, leading to chemo-induced autophagy and chemoresistance in GC cells. MALAT1 promotes autophagy-associated chemoresistance of GC cells via sequestration of miR23b-3p.

Key Molecule: hsa-mir-145 [37]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-145 exerts tumor-suppressive and chemo-resistance lowering effects by targeting CD44 in gastric cancer.

Key Molecule: hsa-mir-27b [38]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/FU cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: LncRNA urothelial carcinoma associated 1 (UCA1) increases multi-drug resistance of gastric cancer via downregulating miR27b.

Key Molecule: Urothelial cancer associated 1 (UCA1) [38]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/FU cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC Apoptosis assay
• Mechanism Description: LncRNA urothelial carcinoma associated 1 (UCA1) increases multi-drug resistance of gastric cancer via downregulating miR27b.

Key Molecule: hsa-mir-363 [39]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-363 promotes gastric cancer cells proliferation by inhibiting FBW7 expression and was associated with chemo-resistance of gastric cancer cells. Silencing FBW7 largely phenocopied miR-363-induced resistance to chemotherapy agents and promoted proliferation in gastric cancer cells. In addition, an inverse correlation between miR-363 and FBW7 mRNA expression was observed in gastric cancer tissues.

Key Molecule: hsa-mir-19a [17]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19a/b are upregulated in multidrug-resistant gastric cancer cell line, miR-19a/b suppress the sensitivity of gastric cancer cells to anticancer drugs, miR-19a/b accelerate the efflux of ADR through P-gp upregulation.

Key Molecule: hsa-mir-19b [17]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19a/b are upregulated in multidrug-resistant gastric cancer cell line, miR-19a/b suppress the sensitivity of gastric cancer cells to anticancer drugs, miR-19a/b accelerate the efflux of ADR through P-gp upregulation.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Transforming growth factor beta 1 (TGFB1) [40]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FAO signaling pathway; Activation; hsa04550
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Enzyme-linked immunosorbent assay
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.

Key Molecule: hsa-miR-145-5p [40]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FAO signaling pathway; Activation; hsa04550
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.

Key Molecule: MACC1 antisense RNA 1 (MACC1-AS1) [40]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FAO signaling pathway; Activation; hsa04550
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Transforming growth factor beta1 (TGF-beta1) secretion by MSCs activated SMAD2/3 through TGF-beta receptors and induced long non-coding RNA (LncRNA) MACC1-AS1 expression in GC cells, which promoted FAO-dependent stemness and chemoresistance through antagonizing miR-145-5p.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [35]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nod/SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA PVT1 can inhibit apoptosis and enhance the 5-Fu resistance via Increasing Bcl2 expression in Gastric Cancer.

Key Molecule: Extracellular matrix receptor III (CD44) [37]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-145 exerts tumor-suppressive and chemo-resistance lowering effects by targeting CD44 in gastric cancer.

Key Molecule: F-box/WD repeat-containing protein 7 (FBXW7) [39]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-363 promotes gastric cancer cells proliferation by inhibiting FBW7 expression and was associated with chemo-resistance of gastric cancer cells. Silencing FBW7 largely phenocopied miR-363-induced resistance to chemotherapy agents and promoted proliferation in gastric cancer cells. In addition, an inverse correlation between miR-363 and FBW7 mRNA expression was observed in gastric cancer tissues.

Key Molecule: Phosphatase and tensin homolog (PTEN) [17]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Inhibition; hsa05235
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19a/b are upregulated in multidrug-resistant gastric cancer cell line, miR-19a/b suppress the sensitivity of gastric cancer cells to anticancer drugs, miR-19a/b accelerate the efflux of ADR through P-gp upregulation.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [41]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Bromodeoxyuridine incorporation assay; Flow cytometry assay; Transwell assay
• Mechanism Description: Down-regulation of HOTAIR could promote chemosensitivity, induce apoptosis of GC cells, and significantly inhibit GC cell proliferation, invasion, and metastasis in vivo and in vitro.

Key Molecule: hsa-mir-147 [42]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR147 suppressed the proliferation and enhanced the chemosensitivity of gastric cancer cells to 5-FU by promoting cell apoptosis through directly targeting PTEN and regulating the PI3k/AkT signaling pathway. knockdown of pten reverses the effects of miR147 downregulation on gastric cancer cells.

Key Molecule: hsa-mir-31 [43]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Induction of miR31 in MkN-45 followed by suppression of RhoA expression resulted in increased sensitivity to 5-fluorouracil, inhibition of cell proliferation, and invasion compared to the control groups.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [44]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Silencing LncRNA HULC could enhance chemotherapy induced apoptosis in GC cells.

Key Molecule: hsa-mir-939 [45]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: RAF/MEK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Flow cytometric analysis; Wound-healing, migration and invasion assay
• Mechanism Description: Decreased expression of miR939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEk/ERk pathway. miR939 exerted its function mainly through inhibiting SLC34A2/Raf/MEk/ERk pathway, which is activated in GC.

Key Molecule: hsa-mir-31 [46]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: MkN-45-miR-31 showed an increased sensitivity to 5-FU, decreased migration and cell invasion compared to the control groups and induction of miR-31 expression in MkN-45 caused a significant reduction of E2F6 and SMUG1 genes.

Key Molecule: hsa-mir-31 [47]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: SNU-1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: SNU-5 cells; Gastric; Homo sapiens (Human); CVCL_0078
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-31 triggers G 2/M cell cycle arrest, enhances the chemosensitivity and inhibits migration and invasion of human gastric cancer cells by downregulating the expression of zeste homolog 2 (ZH2).

Key Molecule: hsa-mir-495 [48]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The miR-495 exerts promotive effects on GC chemosensitivity via inactivation of the mTOR signaling pathway by suppressing ERBB2.

Key Molecule: hsa-miR-195-5p [49]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR 195 5p inhibit multi drug resistance of gastric cancer cells via downregulating ZNF139.

Key Molecule: hsa-miR-623 [50]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The restored miR-623 expression could inhibit the proliferation of GC cells and enhance their chemosensitivity to 5-FU via the cell apoptosis pathway and the recovered CCND1 expression counteracted the effects of miR-623 on GC cell proliferation, chemosensitivity, and 5-FU-induced apoptosis.

Key Molecule: Protein lin-28 homolog A (CSDD1) [51]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Lin28/miR107 pathway; Regulation; hsa05206
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.

Key Molecule: Protein lin-28 homolog B (CSDD2) [51]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Lin28/miR107 pathway; Regulation; hsa05206
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.

Key Molecule: hsa-miR-107 [51]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Lin28/miR107 pathway; Regulation; hsa05206
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Lin28 could inhibit the expression of miR-107, thereby up-regulating C-myc, P-gp and down-regulating Cyclin D1, subsequently result in chemo-resistance of gastric cancer cells. The Lin28/miR-107 pathway might be served as one of many signaling pathways that is associated with gastric cancer chemo-resistance.

Key Molecule: hsa-mir-218 [52]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-218 may inhibit efflux of ADM and oxaliplatin by down-regulating P-gp expression.

Key Molecule: hsa-mir-197 [53]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: When miR-197 was overexpressed in SGC7901 cells, the protein levels of MAPk1 were downregulated. Furthermore, MAPk1 knockdown significantly increased the growth inhibition rate of the SGC7901/5-FU cells compared with those in the control group. These results indicated that miR-197 may influence the sensitivity of 5-FU treatment in a gastric cancer cell line by targeting MAPk1.

Key Molecule: hsa-miR-23b-3p [54]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR23b-3p/ATG12/HMGB2/autophagy regulatory loop signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: SCID-SHO mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.

Key Molecule: hsa-miR-508-5p [55]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1.

Key Molecule: hsa-mir-204 [56]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: GTL-16 cells; Gastric; Homo sapiens (Human); CVCL_7668
• In Vivo Model: CD1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil.

Key Molecule: hsa-mir-27a [57]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Tumorigenesis; Inhibition; hsa05200
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulation of miR-27a could also confer sensitivity of drugs on gastric cancer cells, and might increase accumulation and decrease releasing amount of adriamycin in gastric cancer cells. Down-regulation of miR-27a could significantly decrease the expression of P-glycoprotein and the transcriptional activity of cyclin D1, and up-regulate the expression of p21.

Key Molecule: hsa-mir-181 [58]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Solute carrier family 34 member 2 (SLC34A2) [45]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: RAF/MEK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Flow cytometric analysis; Wound-healing, migration and invasion assay
• Mechanism Description: Decreased expression of miR939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEk/ERk pathway. miR939 exerted its function mainly through inhibiting SLC34A2/Raf/MEk/ERk pathway, which is activated in GC.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [52]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-218 may inhibit efflux of ADM and oxaliplatin by down-regulating P-gp expression.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [55]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-30a [59]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC-7901/DDP cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR30a can decrease multidrug resistance (MDR) of gastric cancer cells, miR30a overexpression decreased the expression of P-gp, a MDR-related protein. It is also an important miRNA modulating EMT of the cancer cells.

Key Molecule: Death effector domain-containing protein (DEDD) [60]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The inhibition of miR-17 may have tumor suppressive effects on GC and enhance its chemosensitivity by promoting DEDD, impairing EMT in GC cells.

Key Molecule: hsa-mir-17 [60]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: HGC27 cells; Gastric; Homo sapiens (Human); CVCL_1279
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The inhibition of miR-17 may have tumor suppressive effects on GC and enhance its chemosensitivity by promoting DEDD, impairing EMT in GC cells.

Key Molecule: TGF-beta receptor type II (TGFBR2) [61]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Caspase 3 assay kit
• Mechanism Description: Sensitization of Gastric Cancer Cells to 5-FU by microRNA-204 Through Targeting the TGFBR2-Mediated Epithelial to Mesenchymal Transition.

Key Molecule: hsa-mir-204 [61]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Caspase 3 assay kit
• Mechanism Description: Sensitization of Gastric Cancer Cells to 5-FU by microRNA-204 Through Targeting the TGFBR2-Mediated Epithelial to Mesenchymal Transition.

Key Molecule: Long non-protein coding RNA (LEIGC) [62]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Gastric carcinoma [ICD-11: 2B72.Z]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Overexpression of LEIGC suppressed tumor growth and cell proliferation, and (+) the sensitivity of gastric cancer cells to 5-fluorouracil (5-FU), whereas knockdown of LEIGC showed the opposite effect. We further demonstrated LEIGC functions by inhibiting the epithelial-to-mesenchymal transition (EMT) in gastric cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [42]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR147 suppressed the proliferation and enhanced the chemosensitivity of gastric cancer cells to 5-FU by promoting cell apoptosis through directly targeting PTEN and regulating the PI3k/AkT signaling pathway. knockdown of pten reverses the effects of miR147 downregulation on gastric cancer cells.

Key Molecule: Transforming protein RhoA (RHOA) [43]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis; Immunohistochemical assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Induction of miR31 in MkN-45 followed by suppression of RhoA expression resulted in increased sensitivity to 5-fluorouracil, inhibition of cell proliferation, and invasion compared to the control groups.

Key Molecule: Transcription factor E2F6 (E2F6) [46]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: MkN-45-miR-31 showed an increased sensitivity to 5-FU, decreased migration and cell invasion compared to the control groups and induction of miR-31 expression in MkN-45 caused a significant reduction of E2F6 and SMUG1 genes.

Key Molecule: Single-strand selective monofunctional uracil DNA glycosylase (SMUG1) [46]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: MkN-45-miR-31 showed an increased sensitivity to 5-FU, decreased migration and cell invasion compared to the control groups and induction of miR-31 expression in MkN-45 caused a significant reduction of E2F6 and SMUG1 genes.

Key Molecule: Zeste homolog 2 (ZH2) [47]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: SNU-1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: SNU-5 cells; Gastric; Homo sapiens (Human); CVCL_0078
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-31 triggers G 2/M cell cycle arrest, enhances the chemosensitivity and inhibits migration and invasion of human gastric cancer cells by downregulating the expression of zeste homolog 2 (ZH2).

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [48]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The miR-495 exerts promotive effects on GC chemosensitivity via inactivation of the mTOR signaling pathway by suppressing ERBB2.

Key Molecule: Zinc finger protein with KRAB and SCAN domains 1 (ZKSCAN1) [49]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: MkN28 cells; Gastric; Homo sapiens (Human); CVCL_1416
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR 195 5p inhibit multi drug resistance of gastric cancer cells via downregulating ZNF139.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [50]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The restored miR-623 expression could inhibit the proliferation of GC cells and enhance their chemosensitivity to 5-FU via the cell apoptosis pathway and the recovered CCND1 expression counteracted the effects of miR-623 on GC cell proliferation, chemosensitivity, and 5-FU-induced apoptosis.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [52]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.

Key Molecule: Smoothened homolog (SMO) [52]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Higher miR-218 levels increased the level of Bax and reduced the level of Bcl-2 and miR-218 inhibits multidrug resistance (MDR) of gastric cancer cells by targeting Hedgehog/smoothened.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [53]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: When miR-197 was overexpressed in SGC7901 cells, the protein levels of MAPk1 were downregulated. Furthermore, MAPk1 knockdown significantly increased the growth inhibition rate of the SGC7901/5-FU cells compared with those in the control group. These results indicated that miR-197 may influence the sensitivity of 5-FU treatment in a gastric cancer cell line by targeting MAPk1.

Key Molecule: Ubiquitin-like protein ATG12 (ATG12) [54]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR23b-3p/ATG12/HMGB2/autophagy regulatory loop signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.

Key Molecule: High mobility group protein B2 (HMGB2) [54]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR23b-3p/ATG12/HMGB2/autophagy regulatory loop signaling pathway; Regulation; hsa05206
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.

Key Molecule: DNA-directed RNA polymerase I subunit RPA12 (RPA12) [55]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• In Vitro Model: SGC7901/ADR cells; Gastric; Homo sapiens (Human); CVCL_VU57
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3'-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [56]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: NCI-N87 cells; Gastric; Homo sapiens (Human); CVCL_1603
• In Vitro Model: GTL-16 cells; Gastric; Homo sapiens (Human); CVCL_7668
• In Vivo Model: CD1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-204 targeted Bcl-2 messenger RNA and increased responsiveness of GC cells to 5-fluorouracil and oxaliplatin treatment. Ectopic expression of Bcl-2 protein counteracted miR-204 pro-apoptotic activity in response to 5-fluorouracil.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [57]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric cancer [ICD-11: 2B72.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Tumorigenesis; Inhibition; hsa05200
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulation of miR-27a could also confer sensitivity of drugs on gastric cancer cells, and might increase accumulation and decrease releasing amount of adriamycin in gastric cancer cells. Down-regulation of miR-27a could significantly decrease the expression of P-glycoprotein and the transcriptional activity of cyclin D1, and up-regulate the expression of p21.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [58]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Colon cancer [ICD-11: 2B90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-195 [63]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR195 sensitized resistant cells to 5-FU by downregulating WEE1 and CHk1.

Key Molecule: hsa-miR-15b-5p [64]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. miR15b-5p results in significant reductions in the levels of NF-kB1 and Ikk-alpha, two key modulators in inflammation and cell apoptosis.

Key Molecule: hsa-miR-206 [65]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: miR-206 downregulation modulates 5-FU resistance in HCT116 cells by upregulating Bcl-2.

Key Molecule: hsa-mir-21 [66]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 can mediate the drug resistance to 5-FU by inhibiting its target PDCD4, which can regulate the expression of ABCC5 and CD44 genes.

Key Molecule: Long non-protein coding RNA (snaR) [67]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNU-C4R cells; Colon; Homo sapiens (Human); CVCL_5111
• In Vitro Model: SNU-C5R cells; Colon; Homo sapiens (Human); CVCL_5112
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Down-regulation of snaR decreased cell death after 5-FU treatment, which indicates that snaR loss decreases in vitro sensitivity to 5-FU in human colon cancer cells.

Key Molecule: hsa-mir-21 [68], [69]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HT-29/5-FU cells; Colon; Homo sapiens (Human); CVCL_0I27
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells. And high miR-21 expression was significantly associated with poor therapeutic outcome (P = 0.0001) and adjuvant therapy was associated with improved survival in patients with low miR-21.

Key Molecule: hsa-mir-19b [15]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: KM12C cells; Colon; Homo sapiens (Human); CVCL_9547
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions.

Key Molecule: hsa-mir-34 [4]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/5FU cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase Chk1 (CHK1) [63]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR195 sensitized resistant cells to 5-FU by downregulating WEE1 and CHk1.

Key Molecule: Wee1-like protein kinase (WEE1) [63]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR195 sensitized resistant cells to 5-FU by downregulating WEE1 and CHk1.

Key Molecule: Nuclear factor kappa-B kinase subunit alpha inhibitor (IKKalpha) [64]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Dual-Luciferase Reporter Assay
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. miR15b-5p results in significant reductions in the levels of NF-kB1 and Ikk-alpha, two key modulators in inflammation and cell apoptosis.

Key Molecule: DNA-binding factor KBF1 (p105) (NFKB1) [64]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Dual-Luciferase Reporter Assay
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. miR15b-5p results in significant reductions in the levels of NF-kB1 and Ikk-alpha, two key modulators in inflammation and cell apoptosis.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [65]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: miR-206 downregulation modulates 5-FU resistance in HCT116 cells by upregulating Bcl-2.

Key Molecule: Programmed cell death protein 4 (PDCD4) [66]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 can mediate the drug resistance to 5-FU by inhibiting its target PDCD4, which can regulate the expression of ABCC5 and CD44 genes.

Key Molecule: DNA mismatch repair protein Msh2 (MSH2) [69]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HT-29/5-FU cells; Colon; Homo sapiens (Human); CVCL_0I27
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.

Key Molecule: Myb-related protein B (MYBL2) [15]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: KM12C cells; Colon; Homo sapiens (Human); CVCL_9547
• Experiment for Molecule Alteration: mRNA immunoprecipitation assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions.

Key Molecule: Splicing factor/proline/glutamine-rich (SFPQ) [15]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: KM12C cells; Colon; Homo sapiens (Human); CVCL_9547
• Experiment for Molecule Alteration: mRNA immunoprecipitation assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions.

Key Molecule: Transcription factor E2F3 (E2F3) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/5FU cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3.

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [4]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/5FU cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-338-3p [70]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR338-3p/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR338-3p increased 5-FU resistance by reducing the expression of its target gene, mTOR; and miR338-3p inhibitor sensitized HT29 (mutant p53) and HCT116 p53-/- (deficient p53) cells by activating mTOR; and miR338-3p-mTOR-autophagy was in the competition with 5-FU-induced apoptosis and contributed to the subsequent 5-FU resistance. (Inhibition of mTOR induces autophagy and depresses apoptosis to confer resistance to 5-FU).

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [64]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: Overexpression of XIAP decreases the inhibitory effects of miR15b-5p on drug resistance in colon cancer cells. miR15b-5p mediates NF- B regulation by targeting the anti-apoptosis protein XIAP in vitro.

Key Molecule: hsa-mir-101 [71]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; AO/EB double staining; Transwell invasion assay
• Mechanism Description: Upregulation of miR101 enhances the cytotoxic effect of anticancer drugs through inhibition of colon cancer cell proliferation. The upregulated expression of miR101 inhibited proliferation and migration, and increased the sensitivity of colon cancer cells to chemotherapy.

Key Molecule: hsa-mir-20b [72]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ADAM9/EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT116-R cells; Colon; Homo sapiens (Human); CVCL_AU09
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Annexin V apoptosis assay
• Mechanism Description: miR20b suppresses cell proliferation and apoptosis and regulates cell cycle progression by targeting ADAM9 in HCT116-R cells, miR20b reduces 5-FU resistance by suppressing the ADAM9/EGFR signaling pathway in colon cancer.

Key Molecule: hsa-mir-302a [73]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye-exclusion assay; Annexin V-FITC apoptosis assay; Flow cytometer
• Mechanism Description: Both miR 302a and si IGF 1R inhibited Akt signaling. MiR 302a targeted IGF 1R and enhanced 5 FU induced cell death and viability inhibition in human colon cancer cells.

Key Molecule: hsa-mir-214 [74]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: miR-214 targeted heat shock protein 27 and could sensitize non-resistant colon cancer cells and 5-FU-resistant colon cancer cellsto 5-FU while overexpression of Hsp27 could block miR-214 with an effect on the sensitivity of colon cancer cells to 5-FU.

Key Molecule: hsa-miR-219a-5p [75]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: hsa-mir-494 [76]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: 5-Fu catabolic signaling pathway; Regulation; hsa00983
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-494 also negatively regulated endogenous DPYD expression in SW480 cells. Overexpression or knockdown of DPYD could attenuate miR-494 mediated 5-Fu sensitivity regulation, suggesting the dependence of DPYD regulation in miR-494 activity. miR-494 inhibited SW480/5-Fu derived xenograft tumors growth in vivo at present of 5-Fu.

Key Molecule: hsa-mir-320 [77]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Key Molecule: hsa-mir-34 [78]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LDHA was shown to be a direct target of miR 34a. Overexpression of miR 34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re sensitization of 5 FU resistant cancer cells to 5 FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5 FU, suggesting that the miR 34a induced sensitization to 5 FU is mediated through the inhibition of LDHA. The current study showed that miR 34a is involved in sensitivity to 5 FU in part through its effects on LDHA expression.

Key Molecule: hsa-miR-142-3p [79]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Key Molecule: hsa-mir-140 [24]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [79]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [70]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR338-3p/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR338-3p increased 5-FU resistance by reducing the expression of its target gene, mTOR; and miR338-3p inhibitor sensitized HT29 (mutant p53) and HCT116 p53-/- (deficient p53) cells by activating mTOR; and miR338-3p-mTOR-autophagy was in the competition with 5-FU-induced apoptosis and contributed to the subsequent 5-FU resistance. (Inhibition of mTOR induces autophagy and depresses apoptosis to confer resistance to 5-FU).

Key Molecule: Myeloma cell metalloproteinase (ADAM9) [72]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ADAM9/EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT116-R cells; Colon; Homo sapiens (Human); CVCL_AU09
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Annexin V apoptosis assay
• Mechanism Description: miR20b suppresses cell proliferation and apoptosis and regulates cell cycle progression by targeting ADAM9 in HCT116-R cells, miR20b reduces 5-FU resistance by suppressing the ADAM9/EGFR signaling pathway in colon cancer.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [73]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye-exclusion assay; Annexin V-FITC apoptosis assay; Flow cytometer
• Mechanism Description: Both miR 302a and si IGF 1R inhibited Akt signaling. MiR 302a targeted IGF 1R and enhanced 5 FU induced cell death and viability inhibition in human colon cancer cells.

Key Molecule: Heat shock protein beta-1 (HSPB1) [74]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: miR-214 targeted heat shock protein 27 and could sensitize non-resistant colon cancer cells and 5-FU-resistant colon cancer cellsto 5-FU while overexpression of Hsp27 could block miR-214 with an effect on the sensitivity of colon cancer cells to 5-FU.

Key Molecule: Sal-like protein 4 (SALL4) [75]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: Dihydropyrimidine dehydrogenase [NADP(+)] [76]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: 5-Fu catabolic signaling pathway; Regulation; hsa00983
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-494 also negatively regulated endogenous DPYD expression in SW480 cells. Overexpression or knockdown of DPYD could attenuate miR-494 mediated 5-Fu sensitivity regulation, suggesting the dependence of DPYD regulation in miR-494 activity. miR-494 inhibited SW480/5-Fu derived xenograft tumors growth in vivo at present of 5-Fu.

Key Molecule: Forkhead box protein M1 (FOXM1) [77]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Key Molecule: Lactate dehydrogenase A (LDHA) [78]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LDHA was shown to be a direct target of miR 34a. Overexpression of miR 34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re sensitization of 5 FU resistant cancer cells to 5 FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5 FU, suggesting that the miR 34a induced sensitization to 5 FU is mediated through the inhibition of LDHA. The current study showed that miR 34a is involved in sensitivity to 5 FU in part through its effects on LDHA expression.

Key Molecule: Prominin-1 (PROM1) [79]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Key Molecule: Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) [79]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Key Molecule: Histone deacetylase 4 (HDAC4) [24]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Colorectal cancer [ICD-11: 2B91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR was associated with EZH2, which subsequently suppressed miR-218 expression, and HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-kB signaling in CRC. Thus, HOTAIR may serve as a promising therapeutic target for CRC patients.

Key Molecule: Long non-protein coding RNA 958 (LINC00958) [80]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: BLACAT2 contributes to the cell proliferation, its levels were significantly increased in 5-fluorouracil-resistant cells, and overexpression of BLACAT2 was markedly associated with a low cell inhibition rate.

Key Molecule: hsa-mir-31 [81]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye-exclusion assay
• Mechanism Description: The increased expression level of miR-31 caused 5-FU resistance in colorectal cancer through silencing FIH-1, which is associated with cancer-specific energy metabolism.

Key Molecule: Small nucleolar RNA host gene 15 (SNHG15) [82]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: BALB/c-Rag2/-IL2cc/immunodeficient mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay; Colony formation assay; MTS kit assay
• Mechanism Description: The levels of SNHG15 are related with the capacity of CRC cells to cope with the cytotoxic stress caused by 5-FU, which could be mediated by its interaction with AIF.

Key Molecule: GIHCG inhibitor of miR-200b/200a/429 expression (GIHCG) [83]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Long noncoding RNA GIHCG induces cancer progression and chemoresistance and indicates poor prognosis in colorectal cancer.

Key Molecule: piR-hsa-54265 [84]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: piR-54265 binds PIWIL2 promotes CRC cell proliferation and invasiveness and 5-FU and oxaliplatin resistance via promoting oncogenic STAT3 signaling.

Key Molecule: hsa-let-7a [85]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Transwell assays and wound healing assay; Flow cytometry assay
• Mechanism Description: ANRIL promotes chemoresistance via disturbing expression of ABCC1 by inhibiting the expression of Let-7a in colorectal cancer.

Key Molecule: CDKN2B antisense RNA 1 (CDKN2B-AS1) [85]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Transwell assays and wound healing assay; Flow cytometry assay
• Mechanism Description: ANRIL promotes chemoresistance via disturbing expression of ABCC1 by regulating the expression of Let-7a in colorectal cancer.

Key Molecule: hsa-mir-218 [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: qRT-PCR; luciferase reporter assay;ChIP
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-kB signaling in CRC.

Key Molecule: Cytoskeleton regulator RNA (CYTOR) [86]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Chemoresistance; Activation; hsa05207
• Cell Pathway Regulation: miR139-5p/Notch1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting miR139-5p. LINC00152 could regulate the expression of NOTCH1 through sponging miR139-5p and inhibiting its activity from promoting CRC progression and development.

Key Molecule: hsa-miR-139-5p [86]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR139-5p/Notch1 signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Long non-coding RNA LINC00152 promotes cell proliferation, metastasis, and confers 5-FU resistance in colorectal cancer by inhibiting miR139-5p. LINC00152 could regulate the expression of NOTCH1 through sponging miR139-5p and inhibiting its activity from promoting CRC progression and development.

Key Molecule: Novel transcript, antisense to MYRFL (ENST00000547547) [87]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT116/5-FU cells; Colon; Homo sapiens (Human); CVCL_AU09
• In Vitro Model: LOVO/5-FU cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Knockdown of miR31 increased the 5-FU sensitivity of CRC cells at least partly by upregulation of apoptosis. Overexpression of ENST00000547547 suppressed the anti-apoptotic effect of miR31 via competitive binding to it. ENST00000547547 reduces the 5-FU resistance via competitive binding to miR31 in CRC cells.

Key Molecule: hsa-mir-31 [87]

• Molecule Alteration: Function; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT116/5-FU cells; Colon; Homo sapiens (Human); CVCL_AU09
• In Vitro Model: LOVO/5-FU cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: RNA immunoprecipitation (RIP) assay; Dual-luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Knockdown of miR31 increased the 5-FU sensitivity of CRC cells at least partly by upregulation of apoptosis. Overexpression of ENST00000547547 suppressed the anti-apoptotic effect of miR31 via competitive binding to it. ENST00000547547 reduces the 5-FU resistance via competitive binding to miR31 in CRC cells.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: LncRNA HOTAIR contributes to 5fu resistance through suppressing miR-218 and activating NF-kB/TS signaling in colorectal cancer.

Key Molecule: hsa-mir-218 [2]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• Experiment for Molecule Alteration: qPCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: LncRNA HOTAIR contributes to 5fu resistance through suppressing miR-218 and activating NF-kB/TS signaling in colorectal cancer.

Key Molecule: hsa-mir-135b [88]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT-8/5-FU cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3k/AkT pathway. Inhibition of the PI3k/AkT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU.

Key Molecule: hsa-mir-182 [88]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT-8/5-FU cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3k/AkT pathway. Inhibition of the PI3k/AkT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU.

Key Molecule: Sialyltransferase 7B (SIAT7B) [88]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT-8/5-FU cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Reporter gene assay; RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3k/AkT pathway. Inhibition of the PI3k/AkT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU.

Key Molecule: Long non-protein coding RNA (RP11-708H21.4) [89]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Sequencing assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Overexpressed RP11-708H21.4 suppresses CRC cell proliferation through inducing G1 arrest. Moreover, up-regulation of RP11-708H21.4 inhibits cell migration and invasion, causes cell apoptosis, and enhances 5-FU sensitivity of CRC cells.

Key Molecule: hsa-mir-106a [90]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-106a Reduces 5-Fluorouracil (5-FU) Sensitivity of Colorectal Cancer by downregulating Dual-Specificity Phosphatases 2 (DUSP2).

Key Molecule: Pvt1 oncogene (PVT1) [91]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.

Key Molecule: Pvt1 oncogene (PVT1) [91]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.

Key Molecule: hsa-miR-204-5p [92]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR204-5p ceRNA signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.

Key Molecule: Urothelial cancer associated 1 (UCA1) [92]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR204-5p ceRNA signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR; Northern blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.

Key Molecule: Urothelial cancer associated 1 (UCA1) [92]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR204-5p ceRNA signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR; Northern blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.

Key Molecule: hsa-miR-450b-5p [93]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-450b-5p inhibited stemness and development of chemoresistance to 5-FU by targeting SOX2 in CRC cells.

Key Molecule: RAC serine/threonine-protein kinase (AKT) [94]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR587/PPP2R1B/pAKT/XIAP signaling pathway; Inhibition; hsa05206
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: FET cells; Colon; Homo sapiens (Human); CVCL_A604
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: AkT activation mediated by PPP2R1B contributes to miR-587-conferred 5-FU resistance in colon cancer cells.

Key Molecule: hsa-miR-587 [94]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR587/PPP2R1B/pAKT/XIAP signaling pathway; Inhibition; hsa05206
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: FET cells; Colon; Homo sapiens (Human); CVCL_A604
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: RT-PCR; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by inhibiting PPP2R1B expression in colorectal cancer.

Key Molecule: hsa-mir-520g [95]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p53/miR520g/p21 signaling pathway; Regulation; hsa05206
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: FET cells; Colon; Homo sapiens (Human); CVCL_A604
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: p53 suppresses miR-520g expression and that deletion of p53 up-regulates miR-520g expression. Inhibition of miR-520g in p53 / cells increased their sensitivity to 5-FU treatment. miR-520g conferred resistance to 5-FU-induced apoptosis through the inhibition of p21 expression, which is a direct target of miR-520g. Rescued expression of p21 in miR-520g-expressing colon cancer cells sensitized them to 5-FU-induced apoptosis. Importantly, experiments in tumor xenograft mouse models demonstrate that miR-520g reduced the effectiveness of 5-FU in the inhibition of tumor growth in vivo. Moreover, studies of colorectal cancer specimens indicate a positive correlation between miR-520g expression and chemoresistance.

Key Molecule: hsa-miR-17-5p [96]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT/PI3K signaling pathway; Activation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.

Key Molecule: hsa-mir-19a [97]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Response evaluation criteria in solid tumors assay
• Mechanism Description: Aberrant expression of serum miR-19a in FOLFOX chemotherapy resistance patients, suggesting serum miR-19a could be a potential molecular biomarker for predicting and monitoring resistance to first-line FOLFOX chemotherapy regimens in advanced colorectal cancer patients.

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [98]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR10b/BIM signaling pathway; Activation; hsa05206
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-10b directly inhibits pro-apoptotic BIM, and the overexpression of miR-10b confers chemoresistance in colorectal cancer cells to 5-FU.

Key Molecule: hsa-mir-10b [98]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR10b/BIM signaling pathway; Activation; hsa05206
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-10b directly inhibits pro-apoptotic BIM, and the overexpression of miR-10b confers chemoresistance in colorectal cancer cells to 5-FU.

Key Molecule: hsa-mir-21 [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: FACS analysis
• Mechanism Description: The mismatch repair (MMR) system is involved in DNA damage recognition and repair. Human mutS homolog 2 (hMSH2) and human mutL homolog 1 (hMLH1) function as core MMR proteins and form heterodimers with protein homologs hMSH3 or hMSH6 and hMLH3 or hPMS2, respectively. Colorectal tumors that express a high level of miR-21 display reduced hMSH2 protein expression. Cells that overproduce miR-21 exhibit significantly reduced 5-fluorouracil (5-FU) -induced G2/M damage arrest and apoptosis that is characteristic of defects in the core MMR component.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [85]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Transwell assays and wound healing assay; Flow cytometry assay
• Mechanism Description: ANRIL promotes chemoresistance via disturbing expression of ABCC1 by inhibiting the expression of Let-7a in colorectal cancer.

Key Molecule: ABC-type oligopeptide transporter ABCB9 (ABCB9) [87]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT116/5-FU cells; Colon; Homo sapiens (Human); CVCL_AU09
• In Vitro Model: LOVO/5-FU cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: ENST00000547547 promotes ABCB9 expression by acting as a sponge of miR31 and reduces the 5-FU resistance of CRC cells.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [91]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [91]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Long non-protein coding RNA (CCAL) [99]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin signaling pathway; Activation; hsa04520
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA CCAL can be transferred from CAFs to cancer cells via exosomes, and exosome-enriched CCAL promoted Oxa and 5-FU chemoresistance of CRC cells.

Key Molecule: hsa-miR-1229-5p [100]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: hsa-miR-1246 [100]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: hsa-miR-21-5p [100]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: hsa-miR-96-5p [100]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: Phosphatase and tensin homolog (PTEN) [100]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-1246, miR-21-5p, miR-96-5p and miR-1229-5p from serum exosomes involved in chemotherapy resistance may be new therapeutic targets, downregulating these miRNAs may promote CRC cell sensitivity to chemotherapeutic drugs.

Key Molecule: SLC25A25 antisense RNA 1 (SLC25A25-AS1) [101]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERK/p38 signaling pathway; Inhibition; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: SLC25A25-AS1 overexpression significantly inhibited proliferation and colony formation in colorectal cancer cell lines, and downregulation of SLC25A25-AS1 obviously (+) chemoresistance and promoted EMT process in vitro associated with Erk and p38 signaling pathway activation. Therefore, SLC25A25-AS1 was determined to play a tumor suppressive role in CRC.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [1], [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• Experiment for Molecule Alteration: RIP experiments
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR directly recruits EZH2 and subsequently suppresses miR-218 expression by binding to its promoter and contributes to 5FU resistance through activating NF-kB/TS Signaling in colorectal cancer.

Key Molecule: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) [81]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Trypan blue dye-exclusion assay
• Mechanism Description: The increased expression level of miR-31 caused 5-FU resistance in colorectal cancer through silencing FIH-1, which is associated with cancer-specific energy metabolism.

Key Molecule: Apoptosis-inducing factor 1 (AIFM1) [82]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: BALB/c-Rag2/-IL2cc/immunodeficient mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RIP experiments
• Experiment for Drug Resistance: Flow cytometry assay; Colony formation assay; MTS kit assay
• Mechanism Description: The levels of SNHG15 are related with the capacity of CRC cells to cope with the cytotoxic stress caused by 5-FU, which could be mediated by its interaction with AIF.

Key Molecule: Piwi-like protein 2 (PIWIL2) [84]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: piR-54265 binds PIWIL2 promotes CRC cell proliferation and invasiveness and 5-FU and oxaliplatin resistance via promoting oncogenic STAT3 signaling.

Key Molecule: DNA-binding factor KBF1 (p105) (NFKB1) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: Western blot analysis; luciferase reporter assay;ChIP
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: HOTAIR contributes to 5FU resistance through suppressing miR-218 and activating NF-kB signaling in CRC.

Key Molecule: EGFR-coamplified and overexpressed protein (ECOP) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• Experiment for Molecule Alteration: Western blot analysis; luciferase reporter assay;ChIP
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: VOPP1 overexpression partially reversed the miR-218-induced enhanced susceptibility to 5FU in the HT29 5FU-R subline and HOTAIR knockdown partially reversed 5FU resistance through promoting miR-218 and inactivating NF-kB signaling.

Key Molecule: DNA-binding factor KBF1 (p105) (NFKB1) [2]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: LncRNA HOTAIR contributes to 5fu resistance through suppressing miR-218 and activating NF-kB/TS signaling in colorectal cancer.

Key Molecule: EGFR-coamplified and overexpressed protein (ECOP) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assays
• Mechanism Description: LncRNA HOTAIR contributes to 5fu resistance through suppressing miR-218 and the activation of VOPP1 expression and activating NF-kB/TS signaling in colorectal cancer.

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [89]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Overexpressed RP11-708H21.4 suppresses CRC cell proliferation through inducing G1 arrest. Moreover, up-regulation of RP11-708H21.4 inhibits cell migration and invasion, causes cell apoptosis, and enhances 5-FU sensitivity of CRC cells.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [89]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Overexpressed RP11-708H21.4 suppresses CRC cell proliferation through inducing G1 arrest. Moreover, up-regulation of RP11-708H21.4 inhibits cell migration and invasion, causes cell apoptosis, and enhances 5-FU sensitivity of CRC cells.

Key Molecule: Ribosomal protein S6 kinase beta-1 (RPS6KB1) [89]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Overexpressed RP11-708H21.4 suppresses CRC cell proliferation through inducing G1 arrest. Moreover, up-regulation of RP11-708H21.4 inhibits cell migration and invasion, causes cell apoptosis, and enhances 5-FU sensitivity of CRC cells.

Key Molecule: Dual specificity protein phosphatase 2 (DUSP2) [90]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-106a Reduces 5-Fluorouracil (5-FU) Sensitivity of Colorectal Cancer by downregulating Dual-Specificity Phosphatases 2 (DUSP2).

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [91]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [91]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The overexpression of PVT1 increased the mRNA and protein expression levels of multidrug resistance associated protein 1, P glycoprotein, serine/threonine protein kinase mTOR and apoptosis regulator Bcl2.

Key Molecule: Cyclic AMP-responsive element-binding protein 1 (CREB1) [92]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR204-5p ceRNA signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.

Key Molecule: Transcription factor SOX-2 (SOX2) [93]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-450b-5p inhibited stemness and development of chemoresistance to 5-FU by targeting SOX2 in CRC cells.

Key Molecule: PP2A subunit A isoform R1-beta (PPP2R1B) [94]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR587/PPP2R1B/pAKT/XIAP signaling pathway; Inhibition; hsa05206
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: FET cells; Colon; Homo sapiens (Human); CVCL_A604
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by inhibiting PPP2R1B expression in colorectal cancer.

Key Molecule: Ribonuclease P protein subunit p21 (RPP21) [95]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: p53/miR520g/p21 signaling pathway; Regulation; hsa05206
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: FET cells; Colon; Homo sapiens (Human); CVCL_A604
• In Vitro Model: GEO cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: p53 suppresses miR-520g expression and that deletion of p53 up-regulates miR-520g expression. Inhibition of miR-520g in p53 / cells increased their sensitivity to 5-FU treatment. miR-520g conferred resistance to 5-FU-induced apoptosis through the inhibition of p21 expression, which is a direct target of miR-520g. Rescued expression of p21 in miR-520g-expressing colon cancer cells sensitized them to 5-FU-induced apoptosis. Importantly, experiments in tumor xenograft mouse models demonstrate that miR-520g reduced the effectiveness of 5-FU in the inhibition of tumor growth in vivo. Moreover, studies of colorectal cancer specimens indicate a positive correlation between miR-520g expression and chemoresistance.

Key Molecule: Phosphatase and tensin homolog (PTEN) [96]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT/PI3K signaling pathway; Activation; hsa05235
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The expression level of miRNA-17-5p was found increased in chemoresistant patients. Significantly higher expression levels of miR-17-5p were found in CRC patients with distant metastases and higher clinical stages. kaplan-Meier analysis showed that CRC patients with higher levels of miR-17-5p had reduced survival, especially in patients who had previously received chemotherapy. Overexpression of miR-17-5p promoted COLO205 cell invasiveness. PTEN was a target of miR-17-5p in the colon cancer cells, and their context-specific interactions were responsible for multiple drug-resistance. Chemotherapy was found to increase the expression levels of miR-17-5p, which further repressed PTEN levels, contributing to the development of chemo-resistance.

Key Molecule: DNA mismatch repair protein Msh2 (MSH2) [5]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FACS analysis
• Mechanism Description: The mismatch repair (MMR) system is involved in DNA damage recognition and repair. Human mutS homolog 2 (hMSH2) and human mutL homolog 1 (hMLH1) function as core MMR proteins and form heterodimers with protein homologs hMSH3 or hMSH6 and hMLH3 or hPMS2, respectively. Colorectal tumors that express a high level of miR-21 display reduced hMSH2 protein expression. Cells that overproduce miR-21 exhibit significantly reduced 5-fluorouracil (5-FU) -induced G2/M damage arrest and apoptosis that is characteristic of defects in the core MMR component.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-31 [87]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT116/5-FU cells; Colon; Homo sapiens (Human); CVCL_AU09
• In Vitro Model: LOVO/5-FU cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: RNA immunoprecipitation (RIP) assay; Dual-luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: ABCB9 is a transporter which was reported to be targeted by miR31, involved in cisplatin-induced apoptosis, thus knockdown of miR31 increases the 5-FU sensitivity of CRC cell lines. ENST00000547547 reduces the 5-FU resistance via competitive binding to miR31.

Key Molecule: Novel transcript, antisense to MYRFL (ENST00000547547) [87]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT116/5-FU cells; Colon; Homo sapiens (Human); CVCL_AU09
• In Vitro Model: LOVO/5-FU cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: ABCB9 is a transporter which was reported to be targeted by miR31, involved in cisplatin-induced apoptosis, thus knockdown of miR31 increases the 5-FU sensitivity of CRC cell lines. ENST00000547547 reduces the 5-FU resistance via competitive binding to miR31.

Key Molecule: hsa-miR-874-3p [102]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04391
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Caspase-9 or 3 activity assays; Flow cytometric analysis
• Mechanism Description: Down-regulation of miR874-3p promotes chemotherapeutic resistance in colorectal cancer via inactivation of the Hippo signaling pathway. miR874-3p directly inhibited the expression of transcriptional co-activators YAP and TAZ of the Hippo signaling pathway, resulting in the inactivation of the TEAD transcription.

Key Molecule: hsa-miR-3190-5p [103]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: CHO cells; Ovary; Homo sapiens (Human); CVCL_0213
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ABCC4 was inhibited by miR3190-5p through binding to the 3'-UTR of the ABCC4 gene, this regulatory role of miR3190-5p was disrupted by rs3742106. The rs3742106 T allele offers a binding-site for miR3190-5p, which results in low-expression of ABCC4, increased intracellular concentration of 5-FU, and enhanced sensitivity to 5-FU treatment.

Key Molecule: hsa-miR-196b-5p [104]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: CW-2 cells; Colon; Homo sapiens (Human); CVCL_1151
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Caspase-9 or -3 activity assays; Spheroid formation assay; Flow cytometric analysis; MTT assay
• Mechanism Description: miR196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling.

Key Molecule: Long non-protein coding RNA (RP11-708H21.4) [89]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Overexpressed RP11-708H21.4 suppresses CRC cell proliferation through inducing G1 arrest. Moreover, up-regulation of RP11-708H21.4 inhibits cell migration and invasion, causes cell apoptosis, and enhances 5-FU sensitivity of CRC cells.

Key Molecule: hsa-mir-200c [105]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V/ PI staining; Caspase-3 activity assay
• Mechanism Description: Levels of PTEN and E-cadherin were reduced by knockdown of miR200c in HCT-116 cells, PTEN inactivate the AkT signaling pathway, and E-cadherin is one of the major downstream regulators of miRNA-200c contributing to EMT, which is also important to inhibit tumor invasion and proliferation as well as to induce cell apoptosis.

Key Molecule: hsa-mir-125b [106]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC/PI staining assay
• Mechanism Description: CXCL12/CXCR4 axis induced miR125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer There was a negative correlation of the expression of miR125b with APC mRNA in paired human colorectal tissue specimens. The upregulation of miR125b activated the Wnt/beta-catenin signaling by targeting APC gene and contributed to 5-FU resistance through enhancing cell autophagy.

Key Molecule: hsa-miR-577 [107]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay; Flow cytometric analysis
• Mechanism Description: Ectopic expression of miR577 enhanced 5-FU sensitivity in SW480/5-FU cells by down-regulating HSP27. Enforced expression of HSP27 reversed the effects of miR577 on CRC cell growth and 5-FU sensitivity.

Key Molecule: hsa-mir-141 [108]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTS assay
• Mechanism Description: miR141 inhibited CRC cell proliferation via targeting cyclin D2, which is involved in cell cycle regulation, and inhibited the mainte.nce of CSC stemness, thereby enhancing drug susceptibility.

Key Molecule: hsa-miR-139-5p [109]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal carcinoma [ICD-11: 2B91.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: miR139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells.

Key Molecule: hsa-miR-543 [110]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-543 enhanced drug resistance by down-regulating the expression of phosphatase and tensin homolog (PTEN), which negatively regulates protein kinase B (AkT) activation while an elevated expression of PTEN reversed the chemoresistance of miR-543-overexpressing HCT8 cells to 5-FU.

Key Molecule: hsa-miR-195-5p [111]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT-160 cells; Colorectal; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity
• Mechanism Description: miR-195-5p regulates CRC cell stemness and 5-FU resistance through Notch2 and RBPJ.

Key Molecule: AT-rich interactive domain-containing protein 4B (ARID4B) [112]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-519b-3p mimics promoted HCT116 and SW480 cells more sensitive to chemoradiation treatment while ectopic expression of ARID4B in the meantime decreased the sensitivity.

Key Molecule: hsa-miR-519b-3p [112]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-519b-3p mimics promoted HCT116 and SW480 cells more sensitive to chemoradiation treatment while ectopic expression of ARID4B in the meantime decreased the sensitivity.

Key Molecule: hsa-miR-761 [113]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-761 suppressed colorectal cancer cell proliferation and invasion by downregulating FOXM1.

Key Molecule: hsa-mir-497 [114], [115]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miRNA-497 targeted Smurf1 in CRC cells and the Smurf1 expression level was dramatically increased in neoadjuvant therapy-resistant patients compared with treatment-sensitive patients. These results indicate that down-regulation of miRNA-497 in colorectal cancer may contribute to the resistance of CRC cells to 5-FU treatment. Thus, miRNA-497 has the potential to be a novel biomarker for predicting the neoadjuvant chemotherapy sensitivity in CRC patients.

Key Molecule: hsa-mir-149 [116]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; hsa04150
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reduced miR-149 is a critical factor in the mechanisms by which CRC cells resist the cytotoxicity of 5-FU. Also, re-expression of miR-149 could increase the 5-FU sensitivity of CRC cells via enhancing 5-FU-inducing apoptosis by targeting FOXM1.

Key Molecule: hsa-mir-874 [117]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-874 inhibits growth, increases apoptosis and enhances chemosensitivity in CRC cells by targeting XIAP.

Key Molecule: hsa-miR-139-5p [118]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF-1R/AKT/S6 signaling pathway; Inhibition; hsa05225
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: Ectopic expression of miR-139-5p sensitized CRC cells to 5-FU by increasing 5-FU-induced apoptosis. In addition, miR-139-5p inhibited the expression of the miR-139-5p target gene NOTCH-1 and its downstream molecules MRP-1 and BCL-2, two key MDR-associated genes. Furthermore, silencing NOTCH-1 expression promoted the chemotherapeutic effects of 5-FU, and up-regulation of NOTCH-1 abrogated miR-139-5p-mediated sensitization to 5-FU in LoVo and HCT-116 cells.

Key Molecule: hsa-miR-204-5p [92]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: UCA1/miR204-5p ceRNA signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Northern blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.

Key Molecule: hsa-miR-425-5p [119]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: miR-425-5p is up-regulated in HCT116-R cells with acquired resistance to 5-fluouracil and OX compared with the parental HCT116 cells. Inhibition of miR-425-5p increases sensitivity to anti-cancer drugs by regulating apoptosis-related protein PDCD10 both in vitro and in vivo.

Key Molecule: hsa-mir-22 [120]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: Trypan blue exclusion assay
• Mechanism Description: Tumor cells undergoing autophagy may affect the sensitivity of 5-FU by repressing miR-22 expression. miR-22 will facilitate 5-FU to kill tumor cells when it was exotically introduced into the tumor cells, and tumor cells with higher levels of miR-22 were more sensitive to 5-FU. starvation induced up-regulation of BTG1 in CRC cells was inversely correlated with miR-22, which further demonstrated that miR-22 may influence cells under stress. More importantly, BTG1 can reverse the inhibition of autophagy induced by overexpression of miR-22, and the knockdown of BTG1 can reduce the level of autophagy resulting from the down-regulation of miR-22 in CRC cells with 5-FU treatment. Similarly, the data from clinical samples indicated that the miR-22 level was inversely correlated with the expression of BTG1, and the tumors with higher miR-22 level were more sensitive to 5-FU.

Key Molecule: hsa-mir-23a [121]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: APAF-1/caspase-9 apoptotic signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-23a may inhibit 5-FU-induced apoptosis through the APAF-1/caspase-9 pathway and provide new insight into CRC treatment.

Key Molecule: hsa-mir-34 [122]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: A real-time cell analyzer assay
• Mechanism Description: c-KIT was shown to mediate chemo-resistance (kike 5-FU) in ovarian tumor initiating cells, miR-34a inhibits Erk signaling and colony formation by down-regulation of c-kit, miR-34a can inhibit this effect via down-regulation of c-kit and therefore sensitize cells to chemotherapeutic treatment.

Key Molecule: hsa-mir-129 [123]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: CRC nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: microRNA-129 (miR-129) trigger apoptosis by suppressing key anti-apoptotic protein, B-cell lymphoma 2 (BCL2), enhanced the cytotoxic effect of 5-fluorouracil both in vitro and in vivo.

Key Molecule: hsa-mir-497 [124]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: HCT28 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: IGF1-R has an important role in mediating activation of the PI3k/Akt pathway, miR-497 inhibits PI3k/Akt signalling. Down-regulation of miR-497 is an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.

Key Molecule: hsa-mir-222 [125]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal carcinoma [ICD-11: 2B91.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: ADAM-17 (a desintegrin and metalloproteases 17) is a novel multidrug resistance (MDR) mechanism in multidrug-resistant colorectal carcinoma (CRC). The presence of miR-222 was consistently inversely proportionate to the expression levels of ADAM-17. The loss of miR-222 in the HCT116/L-OHP and HCT-8/VCR MDR cell lines contributed to the overexpression of ADAM-17 and sensitized the HCT116/L-OHP and HCT-8/VCR MDR cells to some anticancer drugs.

Key Molecule: hsa-mir-20a [126]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-20a overexpression resulted in resistance to these chemotherapy agents, while miR-20a knockdown led to sensitization, miR-20a down-regulated both BNIP2 mRNA and BNIP2 protein levels. miR-20a down-regulated the expression of the proapoptotic factor BNIP2, leading to an imbalance of anti-apoptosis and pro-apoptosis factors, resulting in the blockage of events leading to apoptosis.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-218 [127]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Boyden chambers cell migration and invasion assays
• Mechanism Description: miR218 is a tumor-suppressor gene and could significantly suppress the EMT process, miR218 promoted cell apoptosis and enhanced 5-FU-based chemosensitivity in colorectal cancer cells by targeting BIRC5.

Key Molecule: hsa-miR-139-5p [128]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCL2 signaling pathway; Regulation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: BCL2 is a direct target of miR-139-5p in colorectal cancer cells and showed that the tumour suppressor activity of miR-139-5p is mediated by the modulation of BCL2 expression. BCL2 family proteins regulate and contribute to programmed cell death or apoptosis. The cell apoptosis results showed the induction of apoptotic cells contributed greatly to 5-Fu and OXA drug sensitivity, which was consistent with the multidrug resistance mechanisms. miR-139-5p is downregulated in colorectal cancer cells and tissues, and its inhibitory effects on cell migration, invasion, and drug sensitivity are mediated by the downregulation of its target BCL2.

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [129]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT asssay; Innocyte invasion assay
• Mechanism Description: microRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic kRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 kRAS WT cells phenocopied kRAS mutation, increased kRAS activity and ERk and AkT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing kRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells.

Key Molecule: GTPase KRas (KRAS) [129]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT asssay; Innocyte invasion assay
• Mechanism Description: microRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic kRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 kRAS WT cells phenocopied kRAS mutation, increased kRAS activity and ERk and AkT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing kRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells.

Key Molecule: hsa-mir-224 [129]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT asssay; Innocyte invasion assay
• Mechanism Description: microRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic kRAS WT and mutant HCT116 cells. Antagomir-mediated miR-224 silencing in HCT116 kRAS WT cells phenocopied kRAS mutation, increased kRAS activity and ERk and AkT phosphorylation. 5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing kRAS and BRAF mutant proteins. Bioinformatics analysis of predicted miR-224 target genes predicted altered cell proliferation, invasion and epithelial-mesenchymal transition (EMT) phenotypes that were experimentally confirmed in miR-224 knockdown cells.

Key Molecule: hsa-mir-145 [130]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Trypan blue assay; Sulforhodamine B assay
• Mechanism Description: Inhibition of SNAI2 directly with short hairpin sequence for SNAI2 and miR145 replacement therapy both decreased vimentin expression and increased in vitro 5FU sensitivity.

Key Molecule: Zinc finger protein SNAI2 (SNAI2) [130]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue assay; Sulforhodamine B assay
• Mechanism Description: Inhibition of SNAI2 directly with short hairpin sequence for SNAI2 and miR145 replacement therapy both decreased vimentin expression and increased in vitro 5FU sensitivity.

Key Molecule: hsa-mir-143 [131]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Regulation; hsa04064
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-143 increases the sensitivity of colon cancer cells to 5-fluorouracil, probably acting through extracellular-regulated protein kinase 5/nuclear factor-kB regulated pathways.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tafazzin (TAZ) [102]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04391
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase assay; miRNA immunoprecipitation assay
• Experiment for Drug Resistance: Caspase-9 or 3 activity assays; Flow cytometric analysis
• Mechanism Description: Down-regulation of miR874-3p promotes chemotherapeutic resistance in colorectal cancer via inactivation of the Hippo signaling pathway. miR874-3p directly inhibited the expression of transcriptional co-activators YAP and TAZ of the Hippo signaling pathway, resulting in the inactivation of the TEAD transcription.

Key Molecule: Transcriptional coactivator YAP1 (YAP1) [102]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Activation; hsa04391
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase assay; miRNA immunoprecipitation assay
• Experiment for Drug Resistance: Caspase-9 or 3 activity assays; Flow cytometric analysis
• Mechanism Description: Down-regulation of miR874-3p promotes chemotherapeutic resistance in colorectal cancer via inactivation of the Hippo signaling pathway. miR874-3p directly inhibited the expression of transcriptional co-activators YAP and TAZ of the Hippo signaling pathway, resulting in the inactivation of the TEAD transcription.

Key Molecule: Suppressor of cytokine signaling 1 (SOCS1) [104]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: CW-2 cells; Colon; Homo sapiens (Human); CVCL_1151
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Caspase-9 or -3 activity assays; Spheroid formation assay; Flow cytometric analysis; MTT assay
• Mechanism Description: miR196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling.

Key Molecule: Suppressor of cytokine signaling 3 (SOCS3) [104]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAKT2/STAT3 signaling pathway; Inhibition; hsa04030
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: COLO 320DM cells; Colon; Homo sapiens (Human); CVCL_0219
• In Vitro Model: CW-2 cells; Colon; Homo sapiens (Human); CVCL_1151
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Caspase-9 or -3 activity assays; Spheroid formation assay; Flow cytometric analysis; MTT assay
• Mechanism Description: miR196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling.

Key Molecule: Cadherin-1 (CDH1) [105]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V/ PI staining; Caspase-3 activity assay
• Mechanism Description: Levels of PTEN and E-cadherin were reduced by knockdown of miR200c in HCT-116 cells, PTEN inactivate the AkT signaling pathway, and E-cadherin is one of the major downstream regulators of miRNA-200c contributing to EMT, which is also important to inhibit tumor invasion and proliferation as well as to induce cell apoptosis.

Key Molecule: Phosphatase and tensin homolog (PTEN) [105]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V/ PI staining; Caspase-3 activity assay
• Mechanism Description: Levels of PTEN and E-cadherin were reduced by knockdown of miR200c in HCT-116 cells, PTEN inactivate the AkT signaling pathway, and E-cadherin is one of the major downstream regulators of miRNA-200c contributing to EMT, which is also important to inhibit tumor invasion and proliferation as well as to induce cell apoptosis.

Key Molecule: Adenomatous polyposis coli protein (APC) [106]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC/PI staining assay
• Mechanism Description: CXCL12/CXCR4 axis induced miR125b promotes invasion and confers 5-fluorouracil resistance through enhancing autophagy in colorectal cancer There was a negative correlation of the expression of miR125b with APC mRNA in paired human colorectal tissue specimens. The upregulation of miR125b activated the Wnt/beta-catenin signaling by targeting APC gene and contributed to 5-FU resistance through enhancing cell autophagy.

Key Molecule: Heat shock protein beta-1 (HSPB1) [107]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay; Flow cytometric analysis
• Mechanism Description: Ectopic expression of miR577 enhanced 5-FU sensitivity in SW480/5-FU cells by down-regulating HSP27. Enforced expression of HSP27 reversed the effects of miR577 on CRC cell growth and 5-FU sensitivity.

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [108]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; MTS assay
• Mechanism Description: miR141 inhibited CRC cell proliferation via targeting cyclin D2, which is involved in cell cycle regulation, and inhibited the mainte.nce of CSC stemness, thereby enhancing drug susceptibility.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [109]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal carcinoma [ICD-11: 2B91.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: miR139-5p reverses CD44+/CD133+-associated multidrug resistance by downregulating NOTCH1 in colorectal carcinoma cells.

Key Molecule: Phosphatase and tensin homolog (PTEN) [110]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-543 enhanced drug resistance by down-regulating the expression of phosphatase and tensin homolog (PTEN), which negatively regulates protein kinase B (AkT) activation while an elevated expression of PTEN reversed the chemoresistance of miR-543-overexpressing HCT8 cells to 5-FU.

Key Molecule: Neurogenic locus notch homolog protein 2 (NOTCH2) [111]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT-160 cells; Colorectal; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity
• Mechanism Description: miR-195-5p regulates CRC cell stemness and 5-FU resistance through Notch2 and RBPJ.

Key Molecule: Recombining binding protein suppressor of hairless (RBPJ) [111]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT-160 cells; Colorectal; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity
• Mechanism Description: miR-195-5p regulates CRC cell stemness and 5-FU resistance through Notch2 and RBPJ.

Key Molecule: Forkhead box protein M1 (FOXM1) [113]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-761 suppressed colorectal cancer cell proliferation and invasion by downregulating FOXM1.

Key Molecule: Forkhead box protein M1 (FOXM1) [116]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; hsa04150
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Reduced miR-149 is a critical factor in the mechanisms by which CRC cells resist the cytotoxicity of 5-FU. Also, re-expression of miR-149 could increase the 5-FU sensitivity of CRC cells via enhancing 5-FU-inducing apoptosis by targeting FOXM1.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [128]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCL2 signaling pathway; Regulation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: COLO205 cells; Colon; Homo sapiens (Human); CVCL_F402
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: BCL2 is a direct target of miR-139-5p in colorectal cancer cells and showed that the tumour suppressor activity of miR-139-5p is mediated by the modulation of BCL2 expression. BCL2 family proteins regulate and contribute to programmed cell death or apoptosis. The cell apoptosis results showed the induction of apoptotic cells contributed greatly to 5-Fu and OXA drug sensitivity, which was consistent with the multidrug resistance mechanisms. miR-139-5p is downregulated in colorectal cancer cells and tissues, and its inhibitory effects on cell migration, invasion, and drug sensitivity are mediated by the downregulation of its target BCL2.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [117]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysiss
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-874 inhibits growth, increases apoptosis and enhances chemosensitivity in CRC cells by targeting XIAP.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [118]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF-1R/AKT/S6 signaling pathway; Inhibition; hsa05225
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Ectopic expression of miR-139-5p sensitized CRC cells to 5-FU by increasing 5-FU-induced apoptosis. In addition, miR-139-5p inhibited the expression of the miR-139-5p target gene NOTCH-1 and its downstream molecules MRP-1 and BCL-2, two key MDR-associated genes. Furthermore, silencing NOTCH-1 expression promoted the chemotherapeutic effects of 5-FU, and up-regulation of NOTCH-1 abrogated miR-139-5p-mediated sensitization to 5-FU in LoVo and HCT-116 cells.

Key Molecule: Cyclic AMP-responsive element-binding protein 1 (CREB1) [92]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: UCA1/miR204-5p ceRNA signaling pathway; Regulation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA-UCA1 enhances cell proliferation and 5-fluorouracil resistance in colorectal cancer by inhibiting miR-204-5p.We found that UCA1 was up-regulated in CRCs and negatively correlated with survival time in two CRC cohorts. Further mechanistic studies revealed that UCA1 could sponge endogenous miR-204-5p and inhibit its activity. We also identified CREB1 as a new target of miR-204-5p. The protein levels of CREB1 were significantly up-regulated in CRCs, negatively associated with survival time and positively correlated with the UCA1 expression. The present work provides the first evidence of a UCA1-miR-204-5p-CREB1/BCL2/RAB22A regulatory network in CRC and reveals that UCA1 and CREB1 are potential new oncogenes and prognostic factors for CRC.

Key Molecule: Kinase suppressor of Ras 1 (KSR1) [115]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-497 expression levels were downregulated in human CRC specimens compared to the adjacent normal tissues. miR-497 expression levels were strongly correlated with clinical stages and lymph node metastases. Furthermore, kinase suppressor of ras 1 (kSR1), a known oncogene, was a direct target of miR-497, and kSR1 expression levels were inversely correlated with miR-497 expression levels in human CRC specimens. Overexpression of miR-497 inhibited cell proliferation, migration, invasion and increased chemosensitivity to 5-fluorouracil treatment, whereas forced expression of kSR1 had the opposite effect.

Key Molecule: Programmed cell death protein 10 (PDCD10) [119]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: miR-425-5p is up-regulated in HCT116-R cells with acquired resistance to 5-fluouracil and OX compared with the parental HCT116 cells. Inhibition of miR-425-5p increases sensitivity to anti-cancer drugs by regulating apoptosis-related protein PDCD10 both in vitro and in vivo.

Key Molecule: E3 ubiquitin-protein ligase SMURF1 (SMURF1) [114]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miRNA-497 targeted Smurf1 in CRC cells and the Smurf1 expression level was dramatically increased in neoadjuvant therapy-resistant patients compared with treatment-sensitive patients. These results indicate that down-regulation of miRNA-497 in colorectal cancer may contribute to the resistance of CRC cells to 5-FU treatment. Thus, miRNA-497 has the potential to be a novel biomarker for predicting the neoadjuvant chemotherapy sensitivity in CRC patients.

Key Molecule: B-cell translocation gene 1 (BTG1) [120]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue exclusion assay
• Mechanism Description: Tumor cells undergoing autophagy may affect the sensitivity of 5-FU by repressing miR-22 expression. miR-22 will facilitate 5-FU to kill tumor cells when it was exotically introduced into the tumor cells, and tumor cells with higher levels of miR-22 were more sensitive to 5-FU. starvation induced up-regulation of BTG1 in CRC cells was inversely correlated with miR-22, which further demonstrated that miR-22 may influence cells under stress. More importantly, BTG1 can reverse the inhibition of autophagy induced by overexpression of miR-22, and the knockdown of BTG1 can reduce the level of autophagy resulting from the down-regulation of miR-22 in CRC cells with 5-FU treatment. Similarly, the data from clinical samples indicated that the miR-22 level was inversely correlated with the expression of BTG1, and the tumors with higher miR-22 level were more sensitive to 5-FU.

Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [121]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: APAF-1/caspase-9 apoptotic signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-23a may inhibit 5-FU-induced apoptosis through the APAF-1/caspase-9 pathway and provide new insight into CRC treatment.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [122]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: A real-time cell analyzer assay
• Mechanism Description: c-KIT was shown to mediate chemo-resistance (kike 5-FU) in ovarian tumor initiating cells, miR-34a inhibits Erk signaling and colony formation by down-regulation of c-kit, miR-34a can inhibit this effect via down-regulation of c-kit and therefore sensitize cells to chemotherapeutic treatment.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [123]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: CRC nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST assay
• Mechanism Description: microRNA-129 (miR-129) trigger apoptosis by suppressing key anti-apoptotic protein, B-cell lymphoma 2 (BCL2), enhanced the cytotoxic effect of 5-fluorouracil both in vitro and in vivo.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [124]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: COLO 205 cells; Colon; Homo sapiens (Human); CVCL_0218
• In Vitro Model: HCT28 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: IGF1-R has an important role in mediating activation of the PI3k/Akt pathway, miR-497 inhibits PI3k/Akt signalling. Down-regulation of miR-497 is an important mechanism of upregulation of IGF1-R in CRC cells that contributes to malignancy of CRC.

Key Molecule: TNF alpha converting enzyme (ADAM17) [125]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal carcinoma [ICD-11: 2B91.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: ADAM-17 (a desintegrin and metalloproteases 17) is a novel multidrug resistance (MDR) mechanism in multidrug-resistant colorectal carcinoma (CRC). The presence of miR-222 was consistently inversely proportionate to the expression levels of ADAM-17. The loss of miR-222 in the HCT116/L-OHP and HCT-8/VCR MDR cell lines contributed to the overexpression of ADAM-17 and sensitized the HCT116/L-OHP and HCT-8/VCR MDR cells to some anticancer drugs.

Key Molecule: Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 2 (BNIP2) [126]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Colorectal adenocarcinoma [ICD-11: 2B91.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-20a overexpression resulted in resistance to these chemotherapy agents, while miR-20a knockdown led to sensitization, miR-20a down-regulated both BNIP2 mRNA and BNIP2 protein levels. miR-20a down-regulated the expression of the proapoptotic factor BNIP2, leading to an imbalance of anti-apoptosis and pro-apoptosis factors, resulting in the blockage of events leading to apoptosis.

Key Molecule: Mitogen-activated protein kinase 7 (MAPK7) [131]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Regulation; hsa04064
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-143 increases the sensitivity of colon cancer cells to 5-fluorouracil, probably acting through extracellular-regulated protein kinase 5/nuclear factor-kB regulated pathways.

Pancreatic cancer [ICD-11: 2C10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: DiGeorge syndrome critical region gene 5 (DGCR5) [13]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: HAPC cells; Pancreas; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: DGCR5 and miR320a regulate each other in a reciprocal manner and that DGCR5 reverses the inhibition of PDCD4 by miR320a, which is involved in the regulation of the PDAC cell phenotype and response to 5-FU. miR320a is involved in 5-FU resistance modulated by DGCR5.

Key Molecule: Growth arrest specific 5 (GAS5) [132]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• In Vitro Model: 5-FU cells; Colon; Homo sapiens (Human); CVCL_1846
• In Vitro Model: PATU8988; Pancreas; Homo sapiens (Human); CVCL_1847
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• In Vitro Model: SW1990/GEM cells; Pancreas; Homo sapiens (Human); CVCL_ZW98
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: GAS5 regualtes Hippo signaling pathway via miR181c-5p to antagonize the development of multidrug resistance in pancreatic cancer cells. GAS5 regulated chemoresistance and Hippo pathway of pancreatic cancer cells via miR181c-5p/Hippo.

Key Molecule: hsa-miR-221-3p [133]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• In Vitro Model: 293TN cells; Pancreas; Homo sapiens (Human); CVCL_UL49
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: 5-FU and gemcitabine assay; CCK8 assay; Wound healing assay; Transwell chamber invasion assay
• Mechanism Description: miRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1. miR221-3p down-regulated RB1 expression by directly binding to its 3'-UTR and therefore caused increased several aspects of pancreatic cancer pathogenesis, including proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT).

Key Molecule: Urothelial cancer associated 1 (UCA1) [134]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: Capan-1 cells; Pancreas; Homo sapiens (Human); CVCL_0237
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• In Vitro Model: CFPAC1 cells; Pancreas; Homo sapiens (Human); CVCL_1119
• In Vitro Model: HPAC cells; Pancreas; Homo sapiens (Human); CVCL_3517
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Wound-healing assay
• Mechanism Description: CUDR overexpression inhibits cell apoptosis and promotes drug resistance in PDAC and CUDR overexpression in Panc-1 cells significantly increased phosphorylated (p-) focal adhesion kinase (FAk) and p-AkT levels, whereas the total FAk and AkT were not altered compared with in Panc-1 cells transfected with an empty vector.

Key Molecule: hsa-mir-21 [135]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; hsa04151
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• In Vitro Model: 293TN cells; Pancreas; Homo sapiens (Human); CVCL_UL49
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-21 regulates 5-FU drug resistance in pancreatic cancer by reducing the expression of its targets, PTEN and PDCD4. And PTEN and PDCD4, as tumor suppressors, not only can inhibit tumor growth and invasion, but also can downregulate the 5-FU resistance induced by miR-21 in pancreatic cancer cells.

Key Molecule: hsa-mir-181c [136]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Regulation; hsa04392
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and (+) expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival.

Key Molecule: hsa-miR-1246 [21]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Panc1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR-1246 expression via CCNG2. In vivo, we found that miR-1246 could increase tumour-initiating potential and induced drug resistance. A high expression level of miR-1246 was correlated with a worse prognosis and CCNG2 expression was significantly lower in those patients. miR-1246 expression was associated with chemoresistance and CSC-like properties via CCNG2, and could predict worse prognosis in pancreatic cancer patients.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-320 [137]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Wound Healing assay; Matrigel transmembrane invasion assay
• Mechanism Description: miR-320a was up-regulated in 5-FU resistant pancreatic cancer cells and that miR-320a could promote pancreatic cancer cell proliferation, migration and invasion then contributed to the increased 5-FU resistance. Researchers think miR-320a could suppress cell apoptosis by inhibiting PDCD4 and further contribute to drug-resistance, which will be studied in future.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Retinoblastoma-associated protein (RB1) [133]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• In Vitro Model: 293TN cells; Pancreas; Homo sapiens (Human); CVCL_UL49
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: 5-FU and gemcitabine assay; CCK8 assay; Wound healing assay; Transwell chamber invasion assay
• Mechanism Description: miRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1. miR221-3p down-regulated RB1 expression by directly binding to its 3'-UTR and therefore caused increased several aspects of pancreatic cancer pathogenesis, including proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT).

Key Molecule: RAC serine/threonine-protein kinase (AKT) [134]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: Capan-1 cells; Pancreas; Homo sapiens (Human); CVCL_0237
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• In Vitro Model: CFPAC1 cells; Pancreas; Homo sapiens (Human); CVCL_1119
• In Vitro Model: HPAC cells; Pancreas; Homo sapiens (Human); CVCL_3517
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Wound-healing assay
• Mechanism Description: CUDR overexpression inhibits cell apoptosis and promotes drug resistance in PDAC and CUDR overexpression in Panc-1 cells significantly increased phosphorylated (p-) focal adhesion kinase (FAk) and p-AkT levels, whereas the total FAk and AkT were not altered compared with in Panc-1 cells transfected with an empty vector.

Key Molecule: Mitogen-activated protein kinase (MAPK) [134]

• Molecule Alteration: Phosphorylation; Up-regulation
• Resistant Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: Capan-1 cells; Pancreas; Homo sapiens (Human); CVCL_0237
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• In Vitro Model: CFPAC1 cells; Pancreas; Homo sapiens (Human); CVCL_1119
• In Vitro Model: HPAC cells; Pancreas; Homo sapiens (Human); CVCL_3517
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Wound-healing assay
• Mechanism Description: CUDR overexpression inhibits cell apoptosis and promotes drug resistance in PDAC and CUDR overexpression in Panc-1 cells significantly increased phosphorylated (p-) focal adhesion kinase (FAk) and p-AkT levels, whereas the total FAk and AkT were not altered compared with in Panc-1 cells transfected with an empty vector.

Key Molecule: Programmed cell death protein 4 (PDCD4) [135], [137]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; hsa04151
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• In Vitro Model: 293TN cells; Pancreas; Homo sapiens (Human); CVCL_UL49
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Wound Healing assay; Matrigel transmembrane invasion assay
• Mechanism Description: miR-21 regulates 5-FU drug resistance in pancreatic cancer by reducing the expression of its targets, PTEN and PDCD4. And PTEN and PDCD4, as tumor suppressors, not only can inhibit tumor growth and invasion, but also can downregulate the 5-FU resistance induced by miR-21 in pancreatic cancer cells.

Key Molecule: Phosphatase and tensin homolog (PTEN) [135]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Regulation; hsa04151
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• In Vitro Model: 293TN cells; Pancreas; Homo sapiens (Human); CVCL_UL49
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-21 regulates 5-FU drug resistance in pancreatic cancer by reducing the expression of its targets, PTEN and PDCD4. And PTEN and PDCD4, as tumor suppressors, not only can inhibit tumor growth and invasion, but also can downregulate the 5-FU resistance induced by miR-21 in pancreatic cancer cells.

Key Molecule: Serine/threonine-protein kinase LATS2 (LATS2) [136]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Regulation; hsa04392
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and (+) expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival.

Key Molecule: MOB kinase activator 1A (MOB1A) [136]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Regulation; hsa04392
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and (+) expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival.

Key Molecule: Serine/threonine-protein kinase 4 (MST1) [136]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Regulation; hsa04392
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and (+) expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival.

Key Molecule: Protein salvador homolog 1 (SAV1) [136]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Regulation; hsa04392
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and (+) expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival.

Key Molecule: Cyclin-G2 (CCNG2) [21]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Panc1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR-1246 expression via CCNG2. In vivo, we found that miR-1246 could increase tumour-initiating potential and induced drug resistance. A high expression level of miR-1246 was correlated with a worse prognosis and CCNG2 expression was significantly lower in those patients. miR-1246 expression was associated with chemoresistance and CSC-like properties via CCNG2, and could predict worse prognosis in pancreatic cancer patients.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-320 [13]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SUDHL-4 cells; Peritoneal effusion; Homo sapiens (Human); CVCL_0539
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: DGCR5 and miR320a regulate each other in a reciprocal manner and that DGCR5 reverses the inhibition of PDCD4 by miR320a, which is involved in the regulation of the PDAC cell phenotype and response to 5-FU. miR320a is involved in 5-FU resistance modulated by DGCR5. DGCR5 reversed the inhibition of the miR320a target gene PDCD4, which in turn inhibited the proliferation, migration and 5-FU resistance of PDAC cells.

Key Molecule: hsa-miR-181c-5p [132]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SW1990 cells; Pancreas; Homo sapiens (Human); CVCL_1723
• In Vitro Model: 5-FU cells; Colon; Homo sapiens (Human); CVCL_1846
• In Vitro Model: PATU8988; Pancreas; Homo sapiens (Human); CVCL_1847
• In Vitro Model: PATU8988 cells; Pancreas; Homo sapiens (Human); CVCL_1846
• In Vitro Model: SW1990/GEM cells; Pancreas; Homo sapiens (Human); CVCL_ZW98
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long non-coding RNA GAS5 antagonizes the chemoresistance of pancreatic cancer cells through down-regulation of miR181c-5p. GAS5 negatively regulated miR181c-5p, and miR181c-5p dramatically promoted pancreatic cancer cell chemoresistance through inactivating the Hippo signaling.

Key Molecule: hsa-mir-21 [138]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Pancreatic cancer [ICD-11: 2C10.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: PANC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0480
• In Vitro Model: HPAC cells; Pancreas; Homo sapiens (Human); CVCL_3517
• In Vitro Model: HPAF-II cells; Pancreatic; Homo sapiens (Human); CVCL_0313
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SRB (sulforhodamine-B) assay
• Mechanism Description: Low miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro.

Liver cancer [ICD-11: 2C12]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-33a [139]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Colorectal neoplasia differentially expressed (CRNDE) [139]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: hsa-miR-200a-3p [140]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay; Flow cytometric analysis; Colony forming assay
• Mechanism Description: miR200a-3p enhances anti-cancer drug resistance by decreasing DUSP6 expression.

Key Molecule: Hepatocellular carcinoma up-regulated long non-coding RNA (HULC) [141]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells. HULC inhibits the expression and activity of miR6825-5p, miR6845-5p and miR6886-3p.

Key Molecule: hsa-miR-6825-5p [141]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6845-5p [141]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-miR-6886-3p [141]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: hsa-mir-503 [142]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 inhibits proliferation making human hepatocellular carcinoma cells susceptible to 5 fluorouracil by targeting EIF4E.

Key Molecule: hsa-mir-122 [18]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatic carcinoma [ICD-11: 2C12.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR122/PCDH20/AKT/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: MHCC97 cells; Liver; Homo sapiens (Human); CVCL_4971
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; RT-qPCR
• Experiment for Drug Resistance: MTT assay; CellTiter 96 Aqueous One Solution cell proliferation assay
• Mechanism Description: Targeting PCDH20 gene by microRNA-122 confers 5-FU resistance in hepatic carcinoma. Rescue of PCDH20 expression in miR122-expressing cells decreases Akt and mTOR phosphorylation, re-sensitizing hepatocellular carcinoma cell to 5-fluorouracil induced apoptosis.

Key Molecule: hsa-mir-21 [10]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Phosphatase and tensin homolog (PTEN) [143]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: Bel/5-FU cells; Liver; Homo sapiens (Human); CVCL_5493
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Wound healing assay; Transwell assay
• Mechanism Description: Over-expression of miR-32-5p activated the PI3k/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition.

Key Molecule: hsa-miR-32-5p [143]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: Bel/5-FU cells; Liver; Homo sapiens (Human); CVCL_5493
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Wound healing assay; Transwell assay
• Mechanism Description: Over-expression of miR-32-5p activated the PI3k/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition.

Key Molecule: Small nucleolar RNA host gene 6 (SNHG6) [144]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: HCC-LM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8; Flow cytometry assay; EdU assay
• Mechanism Description: Ectopic expression of SNHG6-003 in HCC cells promoted cell proliferation and induced drug resistance, whereas SNHG6-003 knockdown promoted apoptosis. Moreover, SNHG6-003 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-26a/b and thereby modulating the expression of transforming growth factor-beta-activated kinase 1 (TAk1). Importantly, expression analysis revealed that both SNHG6-003 and TAk1 were upregulated in human cancers, exhibiting a co-expression pattern. In HCC patients, high expression of SNHG6-003 closely correlated with tumor progression and shorter survival.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: High mobility group protein HMGI-C (HMGA2) [139]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Luciferase activity assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Downregulated LncRNA CRNDE could up-regulate miR-33a expression and inhibit HMGA2 expression, thus it could significantly promote apoptosis of liver cancer drug-resistant cells on different chemotherapeutic drugs (ADM, DDP, 5-FU)and inhibit its proliferation, migration, invasion and drug resistance.

Key Molecule: Dual specificity protein phosphatase 6 (DUSP6) [140]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometric analysis; Colony forming assay
• Mechanism Description: miR200a-3p enhances anti-cancer drug resistance by decreasing DUSP6 expression.

Key Molecule: Ubiquitin carboxyl-terminal hydrolase 22 (USP22) [141]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR6825-5p, miR6845-5p and miR6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. The pathway 'HULC/USP22/Sirt1/ protective autophagy' attenuates the sensitivity of HCC cells to chemotherapeutic agents.

Key Molecule: Eukaryotic translation initiation factor 4E (EIF4E) [142]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: L02 cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR503 inhibits proliferation making human hepatocellular carcinoma cells susceptible to 5 fluorouracil by targeting EIF4E.

Key Molecule: Protocadherin-20 (PCDH20) [18]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatic carcinoma [ICD-11: 2C12.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR122/PCDH20/AKT/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: MHCC97 cells; Liver; Homo sapiens (Human); CVCL_4971
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; CellTiter 96 Aqueous One Solution cell proliferation assay
• Mechanism Description: Targeting PCDH20 gene by microRNA-122 confers 5-FU resistance in hepatic carcinoma. Rescue of PCDH20 expression in miR122-expressing cells decreases Akt and mTOR phosphorylation, re-sensitizing hepatocellular carcinoma cell to 5-fluorouracil induced apoptosis.

Key Molecule: Nuclear receptor subfamily 2 group C2 (NR2C2) [144]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: HCC-LM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8; Flow cytometry assay; EdU assay
• Mechanism Description: Ectopic expression of SNHG6-003 in HCC cells promoted cell proliferation and induced drug resistance, whereas SNHG6-003 knockdown promoted apoptosis. Moreover, SNHG6-003 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-26a/b and thereby modulating the expression of transforming growth factor-beta-activated kinase 1 (TAk1). Importantly, expression analysis revealed that both SNHG6-003 and TAk1 were upregulated in human cancers, exhibiting a co-expression pattern. In HCC patients, high expression of SNHG6-003 closely correlated with tumor progression and shorter survival.

Key Molecule: Programmed cell death protein 4 (PDCD4) [10]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Key Molecule: Phosphatase and tensin homolog (PTEN) [10]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: PLC/PRF/5 cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: HLE cells; Liver; Homo sapiens (Human); CVCL_1281
• In Vitro Model: HLF cells; Liver; Homo sapiens (Human); CVCL_2947
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-alpha/5-FU. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-alpha/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4, miR-21 induces chemoresistance to IFN-alpha and 5-FU, mediated through PETN and PDCD4.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-379 [145]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: Long non-protein coding RNA 607 (LINC00607) [146]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Real-time RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Key Molecule: Long non-protein coding RNA (KRAL) [147]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: hsa-mir-141 [147]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: Long non-protein coding RNA (KRAL) [147]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: hsa-mir-183 [148]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR183/IDH2/SOCS6/HIF1alpha feedback loop signaling pathway; Regulation; hsa05206
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: IDH2 knockdown resulted in significantly increased HIF-1alpha expression in both BEL-7402 and BEL-7402/5-FU cells. knockdown of SOCS6 had similar but stronger effect as miR-183 in promoting MRP2, P-gp, p-STAT3 and HIF-1alpha expression in BEL-7402 cells, while SOCS6 overexpression also showed similar but stronger effect as miR-183 inhibition in reducing MRP2, P-gp, p-STAT3 and HIF-1alpha levels in BEL-7402/5-FU cells. Both SOCS6 overexpression and miR-183 knockdown significantly increased the sensitivity of BEL-7402/5-FU cells to 5-FU. miR-183 overexpression partly abrogated the effect of SOCS6 in enhancing 5-FU sensitivity.

Key Molecule: hsa-mir-133a [149]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-miR-326 [149]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: hsa-let-7b [150]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Let-7b increased 5 FU sensitivity by repressing Bcl xl expression in HCC cells.

Key Molecule: hsa-mir-125b [151]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: THLE-2 cells; Liver; Homo sapiens (Human); CVCL_3803
• In Vitro Model: THLE-3 cells; Liver; Homo sapiens (Human); CVCL_3804
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Compared with 5-FU-sensitive cells, 5-FU-resistant cells exhibited reduced expression levels of miR-125b, and transfection of pre-miR-125b into liver cancer cells resulted in an increased sensitivity of 5-FU-resistant cells to 5-FU. Since drug resistance is a phenotype of malignant cancer cells, the finding that miR-125b expression levels are negatively correlated with 5-FU resistance in HCC cells is consistent with the reported functions of miR-125b. In addition, 5-FU-resistant cells exhibited higher glucose metabolic activity than 5-FU-sensitive cells, and miR-125 was identified to downregulate glucose metabolism by directly targeting Hk II. These results identified miR-125b as a tumor suppressor-like microRNA, which has great potential as a diagnostic and prognostic biomarker.

Key Molecule: hsa-let-7g [152]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cycle; Inhibition; hsa04110
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Let-7g microRNA contributed to an increase of 5-Fu-induced cell cycle inhibit in human hepatoma cell and sensitized cells to 5-Fu, leading to increased the effectiveness of the drug in treating hepatoma cancer.

Key Molecule: hsa-mir-101 [153]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-101-mediated EZH2 silencing sensitized hepatoblastoma cells to 5-FU- and doxorubicin-induced apoptosis, whereas antagomiR-mediated downregulation of endogenous miR-101 reversed the pro-apoptotic effect.

Key Molecule: hsa-mir-200b [154]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: hsa-mir-200c [154]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: hsa-miR-193a-3p [155]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: FOCUS cells; Liver; Homo sapiens (Human); CVCL_7955
• In Vitro Model: YY-8103 cells; Liver; Homo sapiens (Human); CVCL_WY40
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression.

Key Molecule: hsa-mir-195 [156]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-195 antisense oligonucleotide induced drug resistance in BEL-7402/5-FU cells. miR-195 overexpression repressed Bcl-w protein level. miR-195, one of the down-regulated miRNAs in BEL-7402/5-FU cells, was demonstrated to play a role in the development of drug resistance in hepatocellular carcinoma cells by targeting the antiapoptotic gene, Bcl-w.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [157]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 analysis; EdU analysis; Boyden chamber assay; Transwell assay; Flow cytometry assay
• Mechanism Description: MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-kB.

Key Molecule: DNA-binding factor KBF1 (p105) (NFKB1) [157]

• Molecule Alteration: Phosphorylation; Down-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 analysis; EdU analysis; Boyden chamber assay; Transwell assay; Flow cytometry assay
• Mechanism Description: MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-kB.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [157]

• Molecule Alteration: Phosphorylation; Down-regulation
• Sensitive Disease: Liver cancer [ICD-11: 2C12.6]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 analysis; EdU analysis; Transwell assay; Flow cytometry assay
• Mechanism Description: MALAT1 deficiency related increase in sensitivity of liver cancer cells was associated with regulation of NF-kB.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [145]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1/IGF1R signaling pathway; Inhibition; hsa05200
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: Propidium Iodide (PI) Staining
• Mechanism Description: IGF1 is a hub gene in HCC and is involved in the p53 signaling pathway regulation. miR379 can sensitize HCC cells to chemotherapeutic reagents via targeting IGF1R and suppressing its expression, and suppressing the IGF1/IGF1R signaling pathway.

Key Molecule: Cellular tumor antigen p53 (TP53) [146]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB p65/p53 signaling pathway; Regulation; hsa04064
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HCCLM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity, inhibiting the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC.

Key Molecule: Kelch-like ECH-associated protein 1 (KEAP1) [147]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Cells with kRAL overexpression exhibited a reversal in the resistance against 5-FU, with a significant decrease in the IC50 and a dramatic increase in cellular apoptosis, while silencing keap1 or ectopically expressing miR-141 partially rescued this effect.

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [149], [150]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial signaling pathway; Activation; hsa04217
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; MTT assay
• Mechanism Description: Let-7b increased 5 FU sensitivity by repressing Bcl xl expression in HCC cells. And miR-133a and miR-326 share a common target gene, Bcl-xl. Expression levels of miR-133a and miR-326 are significantly upregulated subsequent to transfection. miR-133a and miR-326 downregulate the mRNA expression of Bcl-xl. miR-133a and miR-326 sensitize HepG2 cells to 5-FU and DDP.

Key Molecule: Suppressor of cytokine signaling 6 (SOCS6) [148]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular cancer [ICD-11: 2C12.4]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR183/IDH2/SOCS6/HIF1alpha feedback loop signaling pathway; Regulation; hsa05206
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: IDH2 knockdown resulted in significantly increased HIF-1alpha expression in both BEL-7402 and BEL-7402/5-FU cells. knockdown of SOCS6 had similar but stronger effect as miR-183 in promoting MRP2, P-gp, p-STAT3 and HIF-1alpha expression in BEL-7402 cells, while SOCS6 overexpression also showed similar but stronger effect as miR-183 inhibition in reducing MRP2, P-gp, p-STAT3 and HIF-1alpha levels in BEL-7402/5-FU cells. Both SOCS6 overexpression and miR-183 knockdown significantly increased the sensitivity of BEL-7402/5-FU cells to 5-FU. miR-183 overexpression partly abrogated the effect of SOCS6 in enhancing 5-FU sensitivity.

Key Molecule: Hexokinase-2 (HK2) [151]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: THLE-2 cells; Liver; Homo sapiens (Human); CVCL_3803
• In Vitro Model: THLE-3 cells; Liver; Homo sapiens (Human); CVCL_3804
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Compared with 5-FU-sensitive cells, 5-FU-resistant cells exhibited reduced expression levels of miR-125b, and transfection of pre-miR-125b into liver cancer cells resulted in an increased sensitivity of 5-FU-resistant cells to 5-FU. Since drug resistance is a phenotype of malignant cancer cells, the finding that miR-125b expression levels are negatively correlated with 5-FU resistance in HCC cells is consistent with the reported functions of miR-125b. In addition, 5-FU-resistant cells exhibited higher glucose metabolic activity than 5-FU-sensitive cells, and miR-125 was identified to downregulate glucose metabolism by directly targeting Hk II. These results identified miR-125b as a tumor suppressor-like microRNA, which has great potential as a diagnostic and prognostic biomarker.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [152]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell cycle; Activation; hsa04110
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Let-7g microRNA contributed to an increase of 5-Fu-induced cell cycle inhibit in human hepatoma cell and sensitized cells to 5-Fu, leading to increased the effectiveness of the drug in treating hepatoma cancer.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [153]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: SNU182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-101-mediated EZH2 silencing sensitized hepatoblastoma cells to 5-FU- and doxorubicin-induced apoptosis, whereas antagomiR-mediated downregulation of endogenous miR-101 reversed the pro-apoptotic effect.

Key Molecule: Rho-associated protein kinase 2 (ROCK2) [154]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: Polycomb protein SUZ12 (SUZ12) [154]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: QBC939 cells; Bile duct; Homo sapiens (Human); CVCL_6942
• In Vitro Model: TFk-1 cells; Bile duct; Homo sapiens (Human); CVCL_2214
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: WST cell counting kit-8
• Mechanism Description: miR-200b/c influenced the tumourigenesis of cholangiocarcinoma cells including their tumour-initiating capacity, sphere formation, and drug resistance (like fluorouracil). We further found that miR-200b/c regulated migration and invasion capacities by directly targeting rho-kinase 2 and regulated tumorigenic properties by directly targeting SUZ12 (a subunit of a polycomb repressor complex).

Key Molecule: Transcription factor E2F1 (E2F1) [155]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: FOCUS cells; Liver; Homo sapiens (Human); CVCL_7955
• In Vitro Model: YY-8103 cells; Liver; Homo sapiens (Human); CVCL_WY40
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression.

Key Molecule: Serine/arginine-rich splicing factor 2 (SRSF2) [155]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: QGY-7703 cells; Liver; Homo sapiens (Human); CVCL_6715
• In Vitro Model: SMMC7721 cells; Uterus; Homo sapiens (Human); CVCL_0534
• In Vitro Model: PLC cells; Liver; Homo sapiens (Human); CVCL_0485
• In Vitro Model: FOCUS cells; Liver; Homo sapiens (Human); CVCL_7955
• In Vitro Model: YY-8103 cells; Liver; Homo sapiens (Human); CVCL_WY40
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. miR-193a-3p Dictates Resistance of Hepatocellular Carcinoma to 5-Fluorouracil via Repression of SRSF2 Expression.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [156]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BEL-7402 cells; Liver; Homo sapiens (Human); CVCL_5492
• In Vitro Model: Bel-7402/5-Fu cells; Liver; Homo sapiens (Human); CVCL_5493
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-195 antisense oligonucleotide induced drug resistance in BEL-7402/5-FU cells. miR-195 overexpression repressed Bcl-w protein level. miR-195, one of the down-regulated miRNAs in BEL-7402/5-FU cells, was demonstrated to play a role in the development of drug resistance in hepatocellular carcinoma cells by targeting the antiapoptotic gene, Bcl-w.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-128 [19]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 clone 23 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1299 clone 41 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The expression of the transcriptional repressor E2F5, a target of miR-128-2, strongly decreases after miR-128-2 exogenous expression. This leads to the abrogation of E2F5 repressive activity on p21waf1 promoter and, consequently, to the transcriptional induction of p21waf1. The newly synthesized p21waf1 protein is mainly localized into the cytoplasmic compartment, where it exerts an anti-apoptotic function in response to anticancer drug treatments.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein LYRIC (MTDH) [19]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: A459 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 clone 23 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: H1299 clone 41 cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The expression of the transcriptional repressor E2F5, a target of miR-128-2, strongly decreases after miR-128-2 exogenous expression. This leads to the abrogation of E2F5 repressive activity on p21waf1 promoter and, consequently, to the transcriptional induction of p21waf1. The newly synthesized p21waf1 protein is mainly localized into the cytoplasmic compartment, where it exerts an anti-apoptotic function in response to anticancer drug treatments.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181 [58]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: CX3C chemokine receptor 1 (CX3CR1) [158]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: D6 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LAX cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LTEP-2 cells; Lung; Homo sapiens (Human); CVCL_6929
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR296-3p inhibited NSCLC cell proliferation, enhance the drug resistance, and apoptosis. Data of luciferase reporter assays demonstrated that the CX3CR1 gene was a direct regulator of tumorsuppressive miR296-3p. Moreover, overexpressed CX3CR1 was confirmed in NSCLC clinical specimens. Inhibition of CX3CR1 could inhibit cancer cellular survival and increase chemotherapy sensitivity. There was a negative relationship between miR296-3p and CX3CR1 expression in NSCLC tissues.

Key Molecule: hsa-miR-296-3p [158]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: SPC-A1 cells; Lung; Homo sapiens (Human); CVCL_6955
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: D6 cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LAX cells; Lung; Homo sapiens (Human); N.A.
• In Vitro Model: LTEP-2 cells; Lung; Homo sapiens (Human); CVCL_6929
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR296-3p inhibited NSCLC cell proliferation, enhance the drug resistance, and apoptosis. Data of luciferase reporter assays demonstrated that the CX3CR1 gene was a direct regulator of tumorsuppressive miR296-3p. Moreover, overexpressed CX3CR1 was confirmed in NSCLC clinical specimens. Inhibition of CX3CR1 could inhibit cancer cellular survival and increase chemotherapy sensitivity. There was a negative relationship between miR296-3p and CX3CR1 expression in NSCLC tissues.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [58]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A549/CDDP cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: LncRNA in non-homologous end joining pathway 1 (LINP1) [159]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance against 5-fluoroutacil and doxorubicin by inhibiting chemotherapeutics-induced apoptosis in breast cancer.

Key Molecule: hsa-mir-149 [160]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: HS signaling pathway; Inhibition; hsa00534
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-149 modulated chemoresistance through targeting the expression of GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST1). With downregulated miR-149, NDST1 expression was increased in chemoresistant MCF-7/ADM cells versus control MCF-7 wild-type cells. The increased NDST1 then activated a heparan sulfate-related pathway involving activation of heparanase. Finally, expression of miR-149 and NDST1 was confirmed in clinical chemoresistant samples of breast cancers receiving anthracycline/taxane-based chemotherapies. The high expression of NDST1 was also an unfavorable predictor for distant relapse-free survival in Her2 and basal breast cancers.

Key Molecule: hsa-mir-204 [161]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Low miR-024 expression was enhancing chemotherapeutic resistance of breast cancer patients.

Key Molecule: hsa-mir-125b [3], [162]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT20 cells; Breast; Homo sapiens (Human); CVCL_0178
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Sphere formation assay
• Mechanism Description: E2F3, and in some settings E2F1, induce apoptosis through p53-dependent or -independent pathways, Overexpression of miR-125b in MCF-7 cells significantly down-regulated E2F3 protein level, overexpression of miR-125b caused a marked inhibition of anticancer drug activity and increased resistance in breast cancer cells in vitro. And elevated miR-125b expression in chemoresistant cancer cells were due to high percentage of SP cells.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: High mobility group protein HMGI-C (HMGA2) [14]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Transwell migration assay
• Mechanism Description: NEAT1 down-regulation decreased the endogenous HMGA2 expression, and HMGA2 down-regulation mimicked LncRNA NEAT1 down-regulation's effect on cell migration, invasion, EMT phenotype and chemo-sensitivity.

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [163]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR4766-5p/SIRT1 signaling pathway; Regulation; hsa05206
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; PE Annexin V assay; TUNEL assay; Invasion assay
• Mechanism Description: The promotion of cell proliferation and metastasis, the acquisition of chemoresistance, and the increased expression of SIRT1 induced by LncRNA-PRLB overexpression could be partly abrogated by ectopic expression of miR-4766-5p.

Key Molecule: SIRT1 regulating LncRNA tumor promoter (SIRLNT) [163]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Chemoresistance; Activation; hsa05207
• Cell Pathway Regulation: miR4766-5p/SIRT1 signaling pathway; Regulation; hsa05206
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Microarray
• Experiment for Drug Resistance: MTT assay; PE Annexin V assay; TUNEL assay; Invasion assay
• Mechanism Description: The promotion of cell proliferation and metastasis, the acquisition of chemoresistance, and the increased expression of SIRT1 induced by LncRNA-PRLB overexpression could be partly abrogated by ectopic expression of miR-4766-5p.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator BAX (BAX) [159]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: Western blot analysis; TUNEL assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance against 5-fluoroutacil and doxorubicin by inhibiting chemotherapeutics-induced apoptosis (apoptosis-related proteins such as caspase-8, caspase-9 and Bax proteins) in breast cancer.

Key Molecule: Caspase-8 (CASP8) [159]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: Western blot analysis; TUNEL assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance against 5-fluoroutacil and doxorubicin by inhibiting chemotherapeutics-induced apoptosis (apoptosis-related proteins such as caspase-8, caspase-9 and Bax proteins) in breast cancer.

Key Molecule: Caspase-9 (CASP9) [159]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: Western blot analysis; TUNEL assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance against 5-fluoroutacil and doxorubicin by inhibiting chemotherapeutics-induced apoptosis (apoptosis-related proteins such as caspase-8, caspase-9 and Bax proteins) in breast cancer.

Key Molecule: Bifunctional heparan sulfate N-deacetylase/sulfotransferase 1 (NDST1) [160]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: HS signaling pathway; Inhibition; hsa00534
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-149 modulated chemoresistance through targeting the expression of GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST1). With downregulated miR-149, NDST1 expression was increased in chemoresistant MCF-7/ADM cells versus control MCF-7 wild-type cells. The increased NDST1 then activated a heparan sulfate-related pathway involving activation of heparanase. Finally, expression of miR-149 and NDST1 was confirmed in clinical chemoresistant samples of breast cancers receiving anthracycline/taxane-based chemotherapies. The high expression of NDST1 was also an unfavorable predictor for distant relapse-free survival in Her2 and basal breast cancers.

Key Molecule: Transcription factor E2F3 (E2F3) [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT20 cells; Breast; Homo sapiens (Human); CVCL_0178
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: E2F3, and in some settings E2F1, induce apoptosis through p53-dependent or -independent pathways, Overexpression of miR-125b in MCF-7 cells significantly down-regulated E2F3 protein level, overexpression of miR-125b caused a marked inhibition of anticancer drug activity and increased resistance in breast cancer cells in vitro.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-320 [164]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TRPC5 signaling pathway; Regulation; hsa05206
• In Vitro Model: MCF-7/ADM cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-320a, which downregulated TRPC5 and NFATC3, colud inreduce chemoresistance.

Key Molecule: Polycomb complex protein BMI-1 (BMI1) [165]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-200c and miR-203 overexpression in breast cancer cells downregulated Bmi1 expression accompanied with reversion of resistance to 5-Fu mediated by Bmi1.

Key Molecule: hsa-mir-200c [165]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-200c and miR-203 overexpression in breast cancer cells downregulated Bmi1 expression accompanied with reversion of resistance to 5-Fu mediated by Bmi1.

Key Molecule: hsa-mir-203 [165]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-453 cells; Breast; Homo sapiens (Human); CVCL_0418
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-200c and miR-203 overexpression in breast cancer cells downregulated Bmi1 expression accompanied with reversion of resistance to 5-Fu mediated by Bmi1.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [14]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Transwell migration assay
• Mechanism Description: NEAT1 promoted invasion through inducing Epithelial-mesenchymal transition (EMT), NEAT1 down-regulation inhibited cell motility and invasion by reversing the EMT phenotype and increased breast cancer cells chemo-sensitivity. There may be a reciprocal repression between miR211 and NEAT1.

Key Molecule: hsa-mir-211 [14]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ZR75-1 cells; Breast; Homo sapiens (Human); CVCL_0588
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Transwell migration assay
• Mechanism Description: NEAT1 promoted invasion through inducing Epithelial-mesenchymal transition (EMT), NEAT1 down-regulation inhibited cell motility and invasion by reversing the EMT phenotype and increased breast cancer cells chemo-sensitivity. There may be a reciprocal repression between miR211 and NEAT1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Nuclear factor of activated T-cells 3 (NFATC3) [164]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TRPC5 signaling pathway; Regulation; hsa05206
• In Vitro Model: MCF-7/ADM cells; Breast; Homo sapiens (Human); CVCL_0031
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR-320a, which downregulated TRPC5 and NFATC3, colud inreduce chemoresistance.

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-206 [166]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: As a potential tumor suppressor, miR206 directly targets CDk4 to suppress the cell growth and enhance the chemotherapy sensitivity to 5-Fu in ovarian cancer cells in vitro.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [166]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: As a potential tumor suppressor, miR206 directly targets CDk4 to suppress the cell growth and enhance the chemotherapy sensitivity to 5-Fu in ovarian cancer cells in vitro.

Cervical cancer [ICD-11: 2C77]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-135a [167]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Promega viability kit assay
• Mechanism Description: Down-regulated of FAk increased sensitivity of HeLa cancer cells to Fluorouracil chemotherapy, targeting and down-regulation of FAk expression by miR-135 and miR-138, overexpressed miR-138 and miR-135 had increased sensitivity to chemotherapy.

Key Molecule: hsa-mir-138 [167]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Promega viability kit assay
• Mechanism Description: Down-regulated of FAk increased sensitivity of HeLa cancer cells to Fluorouracil chemotherapy, targeting and down-regulation of FAk expression by miR-135 and miR-138, overexpressed miR-138 and miR-135 had increased sensitivity to chemotherapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Focal adhesion kinase 1 (FAK1) [167]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega viability kit assay
• Mechanism Description: Down-regulated of FAk increased sensitivity of HeLa cancer cells to Fluorouracil chemotherapy, targeting and down-regulation of FAk expression by miR-135 and miR-138, overexpressed miR-138 and miR-135 had increased sensitivity to chemotherapy.

Kidney cancer [ICD-11: 2C90]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: SET and MYND domain containing 2 (SMYD2) [9]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vivo Model: Balb/c athymic nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: SMYD2 is a histone methyltransferase.The estimated IC50 values of cisplatin, doxorubicin, or 5-FU (but not docetaxel) for AZ505-treated RCC cells were significantly lower than those for the control cells, indicating that the SMYD2 inhibition enhanced the drug sensitivity in renal cancer cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [168]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Key Molecule: hsa-mir-381 [169]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: WEE1/Cdc2 signaling pathway; Activation; hsa04110
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-381 increases sensitivity of 786-O cells to 5-FU by inhibitory WEE1 and increase of Cdc2activity.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death protein 4 (PDCD4) [168]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Key Molecule: Phosphatase and tensin homolog (PTEN) [168]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Key Molecule: Metalloproteinase inhibitor 3 (TIMP3) [168]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Renal carcinoma [ICD-11: 2C90.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• In Vitro Model: RCC10 cells; Kidney; Homo sapiens (Human); CVCL_6265
• In Vitro Model: RCC4 cells; Kidney; Homo sapiens (Human); CVCL_0498
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Celltiter96 Aqueous Non Radioactive Cell Proliferation Assay
• Mechanism Description: Tumor suppressor genes like PTEN, PDCD4 and TIMP3, are target genes of miR21. PTEN is a potent inhibitor of PI3k/Akt pathway, as well as a direct target of miR21.

Key Molecule: Wee1-like protein kinase (WEE1) [169]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Kidney cancer [ICD-11: 2C90.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: WEE1/Cdc2 signaling pathway; Activation; hsa04110
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: HK-2 cells; Kidney; Homo sapiens (Human); CVCL_0302
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-381 increases sensitivity of 786-O cells to 5-FU by inhibitory WEE1 and increase of Cdc2activity.

Head and neck cancer [ICD-11: 2D42]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-let-7d [170]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: FaDu cells; Pharynx; Homo sapiens (Human); CVCL_1218
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Clonogenic assay; MTT assay
• Mechanism Description: The level of let-7d expression is an important factor for cell response to irradiation and chemotherapeutics. Overexpressed let-7d inhibited chemoresistance to cisplatin and paclitaxel in OSCC-ALDH1+ cells.

Key Molecule: hsa-miR-24-3p [171]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: miR-24-3p is involved in regulating cell proliferation, clonogenecity and chemosensitivity in HNSCC cells. CHD5 is the critical downstream mediator implicated in this regulation. Importantly, miR-24-3p is upregulated in HNSCC patient samples. Inhibition of miR-24-3p conferred sensitivity to chemo drugs which was reversed with CHD5 knockdown.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Chromodomain-helicase-DNA-binding protein 5 (CHD5) [171]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SCC15 cells; Tongue; Homo sapiens (Human); CVCL_1681
• Experiment for Molecule Alteration: Northern blotting
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: miR-24-3p is involved in regulating cell proliferation, clonogenecity and chemosensitivity in HNSCC cells. CHD5 is the critical downstream mediator implicated in this regulation. Importantly, miR-24-3p is upregulated in HNSCC patient samples. Inhibition of miR-24-3p conferred sensitivity to chemo drugs which was reversed with CHD5 knockdown.

Metastatic colorectal cancer [ICD-11: 2D85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mediator of RNA polymerase II transcription subunit 12 (MED12) [11]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Middle eastern colorectal cancer [ICD-11: 2D85.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: Whole genome sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Clinical manifestations assay
• Mechanism Description: However, it is worth noting that 50% of MED12-mutated patients with CRC who underwent chemotherapy (4/8) showed poor response to standard chemotherapy.

Key Molecule: Mediator of RNA polymerase II transcription subunit 12 (MED12) [11]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Middle eastern colorectal cancer [ICD-11: 2D85.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: CL34 cells; Colon; Homo sapiens (Human); CVCL_1980
• In Vitro Model: Colo-320 cells; Colon; Homo sapiens (Human); CVCL_1989
• Experiment for Molecule Alteration: Immunoblotted assay; Fluorescence immunostaining assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We also show that MED12 deficiency confers resistance to chemotherapy at the tissue culture level. MED12 is a likely tumour suppressor that modulates TGF-beta-induced epithelial-mesenchymal transition signalling in CRC cell lines.

Key Molecule: Mediator of RNA polymerase II transcription subunit 12 (MED12) [11]

• Molecule Alteration: Mutation; .
• Resistant Disease: Middle eastern colorectal cancer [ICD-11: 2D85.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Inhibition; hsa04350
• Experiment for Molecule Alteration: Whole genome sequencing assay; Next-generation sequencing assay
• Experiment for Drug Resistance: Clinical manifestations assay
• Mechanism Description: However, it is worth noting that 50% of MED12-mutated patients with CRC who underwent chemotherapy (4/8) showed poor response to standard chemotherapy.

Colorectal peritoneal carcinomatosis [ICD-11: 2D91]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Adipocytic Glutamine Synthetase (GS) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Colorectal peritoneal carcinomatosis [CD-11: 2D91.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: B16 cells; Skin; Homo sapiens (Human); CVCL_F936
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: CT26 cells; Colon; Mus musculus (Mouse); CVCL_7254
• In Vitro Model: MC38 cells; Colon; Mus musculus (Mouse); CVCL_B288
• In Vitro Model: SW-480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 3T3-L1 cells; Nasopharynx; Mus musculus (Mouse); CVCL_0123
• In Vivo Model: BALB/c mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Adipocytic Glutamine Synthetase Upregulation via Altered Histone Methylation Promotes 5FU Chemoresistance in Peritoneal Carcinomatosis of Colorectal Cancer

Salivary gland carcinoma [ICD-11: 2E60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Prominin-1 (PROM1) [22]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Salivary gland adenoid cystic carcinoma [ICD-11: 2E60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MET/PI3K/AKT/mTOR signaling pathway; Activation; hsa04150
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: KOA-1 cells; Skin; Homo sapiens (Human); CVCL_L997
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: CD133 activates the PI3K/AKT, AKT/Wnt and other signaling pathways and affects the behavior of CD133+ cells, thereby playing a major role in cancer therapy. In addition, CD133 is also involved in the regulation of tumor resistance. Long-term chemotherapy leads to a significant increase in CD133 expression. Targeting CD133 can reverse drug resistance in colorectal cancer via the AKT/NF-kappa-B/multidrug resistance protein (MDR)1 pathway.

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