Disease Information

General Information of the Disease (ID: DIS00070)

• Name: Esophageal cancer
• ICD: ICD-11: 2B70

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  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 Drug

Approved Drug(s) 14 drug(s) in total

Beta-elemene

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: CDKN2B antisense RNA 1 (CDKN2B-AS1) [1], [2]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Beta-elemene
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Beta-Elemene inhibits the proliferation of esophageal squamous cell carcinoma by regulating long noncoding RNA-mediated inhibition of hTERT expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Telomerase reverse transcriptase (TERT) [1], [2]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Beta-elemene
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Beta-Elemene inhibits the proliferation of esophageal squamous cell carcinoma by regulating long noncoding RNA-mediated inhibition of hTERT expression.

Carboplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [3]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of ATP7A in EC109/cisplatin cells might increase pumping platinum out of cells or binding and sequestration of platinum drugs, then decrease cellular platinum concentration or keep them away from accessing their key cytotoxic targets in the nucleus, finally result in cisplatin-resistance.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Taurine up-regulated 1 (TUG1) [4]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• 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: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 promoted cell resistance to DDP, at least in part, through upregulating Nrf2.

Key Molecule: hsa-miR-455-3p [5]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/beta-catenin/TGF-beta signaling pathway; Activation; hsa04310
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Tumor volume measurement; Luciferase assay
• Mechanism Description: Antagonizing miR455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma. Treatment with a miR455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90+ and CD271+ T-ICs via deactivation of multiple stemness-associated pathways, including Wnt/beta-catenin and TGF-beta signaling.

Key Molecule: hsa-mir-200c [6]

• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical 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: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: 2774 cells; Ovary; Homo sapiens (Human); CVCL_0420
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: KLE cells; Ovary; Homo sapiens (Human); CVCL_1329
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: BRD7 is known to mediate tumor suppression by down-regulation of the beta-catenin pathway through accumulation of beta-catenin in the cytoplasm. miR-200c regulated the translocation of beta-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc, miR-200c induces additive effect on the cisplatin cytotoxicity of endometrial carcinoma cells.

Key Molecule: hsa-mir-141 [7]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: KYSE170 cells; Esophagus; Homo sapiens (Human); CVCL_1358
• In Vitro Model: KYSE190 cells; Esophagus; Homo sapiens (Human); CVCL_8301
• In Vitro Model: KYSE520 cells; Esophagus; Homo sapiens (Human); CVCL_1355
• In Vitro Model: KYSE590 cells; Esophagus; Homo sapiens (Human); CVCL_8508
• In Vitro Model: KYSE890 cells; Esophagus; Homo sapiens (Human); CVCL_A103
• In Vitro Model: KYSE960 cells; Esophagus; Homo sapiens (Human); CVCL_8512
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: When miR-141, which was the most highly expressed miRNA in the cisplatin-resistant cell lines, was expressed ectopically in thecisplatin-sensitive cell lines, cell viability after cisplatin treatment was increased significantly. miR-141 directly targeted the 3 -untranslated region ofYAP1, which is known to have a crucial role in apoptosis inducedby DNA-damaging agents, and thus downregulated YAP1 expression.

Key Molecule: hsa-mir-200c [8]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-200c as the miRNA responsible for chemoresistance in esophageal cancer. knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A (PP2A), which is known to inhibit the phosphorylation of Akt, miR-200c-induced resistance is mediated through the Akt pathway.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [4]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• 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: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 promoted DDP resistance in TE-1 and TE-1/DDP cells by promoting cell proliferation, suppressing cell apoptosis, and elevating protein expression of the classical multi-drug resistance-related P-gp.

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [3]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of ATP7A in EC109/cisplatin cells might increase pumping platinum out of cells or binding and sequestration of platinum drugs, then decrease cellular platinum concentration or keep them away from accessing their key cytotoxic targets in the nucleus, finally result in cisplatin-resistance.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-27a [9]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical 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: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27 in serum originated mainly from esophageal cancer cells, because its serum expression level in patients with esophageal cancer was significantly higher than that of healthy volunteers and decreased significantly after surgery compared with the baseline (before surgery). Moreover, co-culture of fibroblasts with anti-miR-27-transfected esophageal cancer cells resulted in a major decrease in the antiapoptotic function of fibroblasts, compared with fibroblasts co-cultured with control esophageal cancer cells that secrete extracellular miR-27. Serum miR-27 level may reflect the expression level of extracellular miR-27 derived from esophageal cancer cells. miR-27 is involved in resistance to chemotherapy in esophageal cancer, through miR-27 -induced transformation of NOF into CAF, and that TGF-beta secreted from these CAF-like fibroblasts induces chemoresistance to cisplatin in esophageal cancer.

Key Molecule: hsa-mir-27b [9]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical 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: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27 in serum originated mainly from esophageal cancer cells, because its serum expression level in patients with esophageal cancer was significantly higher than that of healthy volunteers and decreased significantly after surgery compared with the baseline (before surgery). Moreover, co-culture of fibroblasts with anti-miR-27-transfected esophageal cancer cells resulted in a major decrease in the antiapoptotic function of fibroblasts, compared with fibroblasts co-cultured with control esophageal cancer cells that secrete extracellular miR-27. Serum miR-27 level may reflect the expression level of extracellular miR-27 derived from esophageal cancer cells. miR-27 is involved in resistance to chemotherapy in esophageal cancer, through miR-27 -induced transformation of NOF into CAF, and that TGF-beta secreted from these CAF-like fibroblasts induces chemoresistance to cisplatin in esophageal cancer.

Key Molecule: TGF-beta receptor type I (TGFBR1) [9]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical 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: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: Elisa assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27 in serum originated mainly from esophageal cancer cells, because its serum expression level in patients with esophageal cancer was significantly higher than that of healthy volunteers and decreased significantly after surgery compared with the baseline (before surgery). Moreover, co-culture of fibroblasts with anti-miR-27-transfected esophageal cancer cells resulted in a major decrease in the antiapoptotic function of fibroblasts, compared with fibroblasts co-cultured with control esophageal cancer cells that secrete extracellular miR-27. Serum miR-27 level may reflect the expression level of extracellular miR-27 derived from esophageal cancer cells. miR-27 is involved in resistance to chemotherapy in esophageal cancer, through miR-27 -induced transformation of NOF into CAF, and that TGF-beta secreted from these CAF-like fibroblasts induces chemoresistance to cisplatin in esophageal cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NFE2-related factor 2 (NRF2) [4]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• 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: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: RNA pull-down assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 promoted cell resistance to DDP, at least in part, through upregulating Nrf2.

Key Molecule: Transcription factor SOX-9 (SOX9) [10]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell motility; Activation; hsa04510
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Self-renewal signaling pathway; Activation; hsa04550
• 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: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• Experiment for Molecule Alteration: Dual luciferase reporter assay; RNA-binding protein immunoprecipitation; Western blot analysis
• Experiment for Drug Resistance: CCK8, colony formation, Transwell, and sphere-forming assay
• Mechanism Description: Linc-ROR modulating the derepression of SOX9 by directly sponging multiple miRNAs including miR15b, miR33a, miR129, miR145, and miR206. Silencing of linc-ROR significantly inhibited cell proliferation, motility, chemoresistance, and self-renewal capacity.

Key Molecule: Bromodomain-containing protein 7 (BRD7) [6]

• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical 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: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• In Vitro Model: HEC-1A cells; Uterus; Homo sapiens (Human); CVCL_0293
• In Vitro Model: 2774 cells; Ovary; Homo sapiens (Human); CVCL_0420
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: KLE cells; Ovary; Homo sapiens (Human); CVCL_1329
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: BRD7 is known to mediate tumor suppression by down-regulation of the beta-catenin pathway through accumulation of beta-catenin in the cytoplasm. miR-200c regulated the translocation of beta-catenin from the cytoplasm to the nucleus via inhibition of BRD7, resulting in increased expression of its transcriptional target genes, cyclinD1 and c-myc, miR-200c induces additive effect on the cisplatin cytotoxicity of endometrial carcinoma cells.

Key Molecule: Transcriptional coactivator YAP1 (YAP1) [7]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: KYSE140 cells; Esophagus; Homo sapiens (Human); CVCL_1347
• In Vitro Model: KYSE170 cells; Esophagus; Homo sapiens (Human); CVCL_1358
• In Vitro Model: KYSE190 cells; Esophagus; Homo sapiens (Human); CVCL_8301
• In Vitro Model: KYSE520 cells; Esophagus; Homo sapiens (Human); CVCL_1355
• In Vitro Model: KYSE590 cells; Esophagus; Homo sapiens (Human); CVCL_8508
• In Vitro Model: KYSE890 cells; Esophagus; Homo sapiens (Human); CVCL_A103
• In Vitro Model: KYSE960 cells; Esophagus; Homo sapiens (Human); CVCL_8512
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: When miR-141, which was the most highly expressed miRNA in the cisplatin-resistant cell lines, was expressed ectopically in thecisplatin-sensitive cell lines, cell viability after cisplatin treatment was increased significantly. miR-141 directly targeted the 3 -untranslated region ofYAP1, which is known to have a crucial role in apoptosis inducedby DNA-damaging agents, and thus downregulated YAP1 expression.

Key Molecule: PP2A subunit A isoform R1-beta (PPP2R1B) [8]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-200c as the miRNA responsible for chemoresistance in esophageal cancer. knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A (PP2A), which is known to inhibit the phosphorylation of Akt, miR-200c-induced resistance is mediated through the Akt pathway.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [11]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [11]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [11]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [11]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-130a-3p [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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: 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 [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; 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 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 [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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 [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: Prostate cancer associated transcript 1 (PCAT1) [13]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of PCAT-1 increased the proliferation rate and growth of OC cells. Inhibition of PCAT-1 decreased proliferation and growth of OC cells, and increased cisplatin chemosensitivity. PCAT-1 promotes development of OC and represses the chemoresistance of OC to cisplatin.

Key Molecule: Mitogen-activated protein kinase kinase kinase 8 (MAP3K8) [10]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: MAPK/BCR/PI signaling pathway; Regulation; hsa04662
• 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: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• In Vitro Model: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: KYSE150 cells; Esophagus; Homo sapiens (Human); CVCL_1348
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8, colony formation, Transwell, and sphere-forming assay
• Mechanism Description: miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Key Molecule: hsa-miR-125a-5p [14]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: STAT3 signaling pathway; Inhibition; hsa04550
• 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: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: EC1 cells; Esophagus; Homo sapiens (Human); CVCL_DC74
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Would healing assay; Invasion assay
• Mechanism Description: miR 125a 5p and cisplatin markedly inactivated the STAT3 signaling pathway.

Key Molecule: hsa-mir-224 [15]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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) [15]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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-187 [16]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PTEN and TNF were demonstrated to be upregulated following miR-187 overexpression. TNF is a cytokine that regulates multiple cellular processes including proliferation and apoptosis. PTEN acts as a tumor suppressor and regulates the PI3k/AkT pathway, which has been identified as a radiation response pathway. The upregulation of PTEN enhances radiosensitivity via the downregulation of the PI3k/AkT pathway.

Key Molecule: hsa-let-7g [17]

• Sensitive Disease: Esophageal carcinoma [ICD-11: 2B70.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs.

Key Molecule: hsa-let-7i [17]

• Sensitive Disease: Esophageal carcinoma [ICD-11: 2B70.4]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs.

Key Molecule: hsa-mir-96 [18]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; 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: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; CCK8 assay
• Mechanism Description: Ectopic overexpression of miR-96 in TE-1 or ECa-109 contributed to tumor growth in xenograft mouse models. Furthermore, up-regulation of miR-96 could reduce the susceptibilities of EC cells to chemotherapy or radiotherapy. RECk was identified as a target of miR-96 and RECk overexpressing could abrogate the growth of EC cells induced by miR-96. Taken together, miR-96 serves as an oncogene role in EC cells through downregulating RECk.

Key Molecule: hsa-mir-200c [19]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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-223 [20]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Key Molecule: hsa-let-7c [21]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: IL6/STAT3 signaling signaling pathway; Inhibition; hsa04659
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vitro Model: TE1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: TE11 cells; Esophagus; Homo sapiens (Human); CVCL_1761
• In Vitro Model: TE5 cells; Esophagus; Homo sapiens (Human); CVCL_1764
• In Vitro Model: TE9 cells; Esophagus; Homo sapiens (Human); CVCL_1767
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Let-7c directly repressed cisplatin-activated interleukin (IL) -6/STAT3 prosurvival pathway, restored sensitivity to cisplatin and increased rate of apoptosis after exposure to cisplatin.

Key Molecule: hsa-mir-148a [22]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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 [22]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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 [23]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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 [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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: ATP-binding cassette sub-family C10 (ABCC10) [17]

• Sensitive Disease: Esophageal carcinoma [ICD-11: 2B70.4]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [23], [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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: MTT 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: Signal transducer activator transcription 3 (STAT3) [14]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• 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: STAT3 signaling pathway; Inhibition; hsa04550
• 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: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• In Vitro Model: EC1 cells; Esophagus; Homo sapiens (Human); CVCL_DC74
• In Vitro Model: KYSE70 cells; Esophagus; Homo sapiens (Human); CVCL_1356
• In Vitro Model: kYSE450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Would healing assay; Invasion assay
• Mechanism Description: miR 125a 5p and cisplatin markedly inactivated the STAT3 signaling pathway.

Key Molecule: Transmembrane protease serine 11E (TM11E) [15]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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.

Key Molecule: Phosphatase and tensin homolog (PTEN) [16]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PTEN and TNF were demonstrated to be upregulated following miR-187 overexpression. TNF is a cytokine that regulates multiple cellular processes including proliferation and apoptosis. PTEN acts as a tumor suppressor and regulates the PI3k/AkT pathway, which has been identified as a radiation response pathway. The upregulation of PTEN enhances radiosensitivity via the downregulation of the PI3k/AkT pathway.

Key Molecule: Tumor necrosis factor (TNF) [16]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• 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: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: PTEN and TNF were demonstrated to be upregulated following miR-187 overexpression. TNF is a cytokine that regulates multiple cellular processes including proliferation and apoptosis. PTEN acts as a tumor suppressor and regulates the PI3k/AkT pathway, which has been identified as a radiation response pathway. The upregulation of PTEN enhances radiosensitivity via the downregulation of the PI3k/AkT pathway.

Key Molecule: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) [18]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; 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: EC9706 cells; Esophagus; Homo sapiens (Human); CVCL_E307
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; CCK8 assay
• Mechanism Description: Ectopic overexpression of miR-96 in TE-1 or ECa-109 contributed to tumor growth in xenograft mouse models. Furthermore, up-regulation of miR-96 could reduce the susceptibilities of EC cells to chemotherapy or radiotherapy. RECk was identified as a target of miR-96 and RECk overexpressing could abrogate the growth of EC cells induced by miR-96. Taken together, miR-96 serves as an oncogene role in EC cells through downregulating RECk.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [20]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Key Molecule: Interleukin-6 (IL6) [21]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: IL6/STAT3 signaling signaling pathway; Inhibition; hsa04659
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TE13 cells; Esophageal; Homo sapiens (Human); CVCL_4463
• In Vitro Model: TE10 cells; Esophagus; Homo sapiens (Human); CVCL_1760
• In Vitro Model: TE1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: TE11 cells; Esophagus; Homo sapiens (Human); CVCL_1761
• In Vitro Model: TE5 cells; Esophagus; Homo sapiens (Human); CVCL_1764
• In Vitro Model: TE9 cells; Esophagus; Homo sapiens (Human); CVCL_1767
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Let-7c directly repressed cisplatin-activated interleukin (IL) -6/STAT3 prosurvival pathway, restored sensitivity to cisplatin and increased rate of apoptosis after exposure to cisplatin.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-455-3p [5]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/beta-catenin/TGF-beta signaling pathway; Activation; hsa04310
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• In Vitro Model: KYSE30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Tumor volume measurement; Luciferase assay
• Mechanism Description: Antagonizing miR455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma. Treatment with a miR455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90+ and CD271+ T-ICs via deactivation of multiple stemness-associated pathways, including Wnt/beta-catenin and TGF-beta signaling.

Key Molecule: hsa-miR-193a-3p [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• 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: Presenilin-1 (PSEN1) [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Docetaxel
• 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.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [11]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [11]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [11]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [11]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200c [19]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Docetaxel
• 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.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-214 [26]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miR-483 and miR-214 might predict less chemotherapy effect. Down-regulation of miR-483 and miR-214 could confer sensitivity of both P-glycoprotein-related and P-glycoprotein-nonrelated drugs to esophageal cancer cells, and it might induce increased accumulation of adriamycin (ADR) and decreased amount of ADR released.

Key Molecule: hsa-mir-483 [26]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miR-483 and miR-214 might predict less chemotherapy effect. Down-regulation of miR-483 and miR-214 could confer sensitivity of both P-glycoprotein-related and P-glycoprotein-nonrelated drugs to esophageal cancer cells, and it might induce increased accumulation of adriamycin (ADR) and decreased amount of ADR released.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [27]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: Flow cytometry assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Extracellular vesicles released by drug-resistant cells were proved that they could upregulate the expression of ABCG2 in esophageal cancer cells and thus regulate the drug resistance of esophageal cancer cells, which was related to the linc-VLDLR carried by EVs.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Very low density lipoprotein receptor (VLDLR) [27]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: ECA-109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Extracellular vesicles released by drug-resistant cells were proved that they could upregulate the expression of ABCG2 in esophageal cancer cells and thus regulate the drug resistance of esophageal cancer cells, which was related to the linc-VLDLR carried by EVs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200c [19]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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-223 [20]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Key Molecule: hsa-mir-296 [23]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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 [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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) [23], [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• 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: MTT 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: Poly[ADP-ribose] synthase 1 (PARP1) [20]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-141-3p [28]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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 [29]

• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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) [28]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• 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) [29]

• Resistant Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• 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) [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• 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 [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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 [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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 [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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 [12]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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) [30]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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 [15]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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) [15]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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 [19]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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 [22]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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 [22]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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 [23]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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 [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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) [23], [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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(+)] [30]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Methylation; Down-regulation
• Sensitive Drug: Fluorouracil
• 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) [15]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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.

Gefitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [31]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gefitinib
• 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
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; hsa05206
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TTn cells; Esophageal; Homo sapiens (Human); CVCL_3175
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.

Key Molecule: Prostate androgen-regulated transcript 1 (PART1) [31]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gefitinib
• 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
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; hsa05206
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TTn cells; Esophageal; Homo sapiens (Human); CVCL_3175
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.

Key Molecule: hsa-mir-129 [31]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Gefitinib
• 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
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; hsa05206
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TTn cells; Esophageal; Homo sapiens (Human); CVCL_3175
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.

Key Molecule: Prostate androgen-regulated transcript 1 (PART1) [31]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gefitinib
• 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
• Cell Pathway Regulation: miR129/BCL2 signaling pathway; Regulation; hsa05206
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: KYSE-450 cells; Esophagus; Homo sapiens (Human); CVCL_1353
• In Vitro Model: TE6 cells; Esophageal; Homo sapiens (Human); CVCL_1765
• In Vitro Model: TE8 cells; Esophageal; Homo sapiens (Human); CVCL_1766
• In Vitro Model: TTn cells; Esophageal; Homo sapiens (Human); CVCL_3175
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: Exosome-mediated transfer of PART1 promoted gefitinib resistance by competitively binding to miR-129 to facilitate Bcl-2 expression in ESCC cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-1 [32]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gefitinib
• 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: PI3K/AKT/survivin signaling pathway; Inhibition; hsa04151
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Exogenous expression of miR 1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIk3CA protein expression levels. Furthermore, overexpression of miR 1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [32]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gefitinib
• 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: PI3K/AKT/survivin signaling pathway; Inhibition; hsa04151
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Exogenous expression of miR 1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIk3CA protein expression levels. Furthermore, overexpression of miR 1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib.

Mitomycin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-223 [20]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Mitomycin
• 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: Cell viability; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [20]

• Sensitive Disease: Esophageal adenocarcinoma [ICD-11: 2B70.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OE33 cellss; Esophagus; Homo sapiens (Human); CVCL_0471
• In Vitro Model: HEEpiC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vitro Model: JHesoAD1 cells; Esophagus; Homo sapiens (Human); CVCL_8098
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The DNA damage repair protein poly(ADP-ribose) polymerase 1 (PARP1) is a bona fide target of miR-223, miR-223 up-regulation is also associated with reduced PARP1 transcripts, and an increased sensitivity to cis-diamminedichloroplatinum (II) (Cisplatin), Doxorubicin and Mitomycin C.

Nimotuzumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [33]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Mutation; .
• Resistant Drug: Nimotuzumab
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• Mechanism Description: NGS examination of this patient demonstrated that PIK3CA mutation and a RICTOR amplification might participate in primary and acquired resistance to nimotuzumab, respectively, via the PI3K/AKT/mTOR signaling pathway.

Key Molecule: Rapamycin-insensitive companion of mTOR (RICTOR) [33]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Structural variation; Amplification
• Resistant Drug: Nimotuzumab
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT/mTOR signaling pathway; Activation; hsa04151
• Mechanism Description: NGS examination of this patient demonstrated that PIK3CA mutation and a RICTOR amplification might participate in primary and acquired resistance to nimotuzumab, respectively, via the PI3K/AKT/mTOR signaling pathway.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-141-3p [28]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• 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.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [3]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of ATP7A in EC109/cisplatin cells might increase pumping platinum out of cells or binding and sequestration of platinum drugs, then decrease cellular platinum concentration or keep them away from accessing their key cytotoxic targets in the nucleus, finally result in cisplatin-resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [28]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• 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: Sphingosine-1-phosphate lyase 1 (SGPL1) [11]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [11]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE33 cells; Esophagus; Homo sapiens (Human); CVCL_0471
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine-1-phosphate lyase 1 (SGPL1) [11]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Key Molecule: Sphingosine kinase 1 (SPHK1) [11]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OE21 cells; Esophagus; Homo sapiens (Human); CVCL_2661
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: S1P could lead to cytotoxic drug resistance in gastroesophegal cancer acting in an autocrine or paracrine manner via cell surface S1P receptors following transportation out of the cytosol. Alternatively S1P may mediate cytotoxic drug resistance acting intracellularly by counteracting apoptosis mediated by its pro-apoptotic precursor ceramide or interaction with known intracellular targets involved in cancer pathogenesis and cytotoxic drug resistance such as Histone deacetylase 1 (HDAC1) and Histone deacetylase 2 (HDAC 2) to which S1P directly binds and inhibits, and TNF Receptor-Associated Factor 2 (TRAF 2), or Protein Kinase C (PKC). S1P production controlled by SPHK1 and SGPL1 are key determinants of cytotoxic drug resistance and that decreasing S1P production in cancer cells could lead to increased cytotoxic sensitivity.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-193a-3p [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Presenilin-1 (PSEN1) [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• 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.

Vincristine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-296 [23]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• 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 [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• 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) [23], [24]

• Sensitive Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; 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.

Vindesine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vindesine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: B16-F10 cells; Skin; Mus musculus (Mouse); CVCL_0159
• In Vitro Model: BHT101 cells; Lymph node; Homo sapiens (Human); CVCL_1085
• In Vitro Model: BHT-101 cells; Thyroid gland; Homo sapiens (Human); CVCL_1085
• In Vitro Model: C2C12 mouse skeletal muscle cells; Skeletal muscle; Mus musculus (Mouse); CVCL_0188
• In Vitro Model: C6 cells; Brain; Rattus norvegicus (Rat); CVCL_0194
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: Caco-2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: CAL-1 [Human plasmacytoid dendritic] cells; Pleural effusion; Homo sapiens (Human); CVCL_5G46
• Experiment for Molecule Alteration: DNA and RNA analysis
• Experiment for Drug Resistance: Colony Formation
• Mechanism Description: In SH-1-V8 cells, cellular accumulation of vincristine decreased and an MDR reversal agent, cepharanthine, potentiated the cytoci-dal action of vindesine. The expression of MDR 1 mRNA was enhanced and amplification of the MDR1 gene was observed in clones SH-1-V4, SH-1-V5, SH-1-V6, SH-1-V7 and SH-1-V8; expression of MDR1 mRNA was detectable without gene amplification in the remaining 3 clones. The enhanced expression of the MDR1 gene may be involved in the acquisition of vindesine resistance in human esophageal cancer cells.

Vinorelbine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-193a-3p [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vinorelbine
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vinorelbine
• 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 [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vinorelbine
• 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: Presenilin-1 (PSEN1) [25]

• Resistant Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Vinorelbine
• 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.

Clinical Trial Drug(s) 1 drug(s) in total

LY-294002

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [35]

• Sensitive Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Drug: LY-294002
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TE cells; Eye; Oreochromis mossambicus (Mozambique tilapia); CVCL_YD05
• In Vitro Model: KYSE cells; N.A.; .; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of LY-294002 by aberration of the drug's therapeutic target

Investigative Drug(s) 1 drug(s) in total

2-Bromo-4-fluorobenzaldehyde

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-127-3p [36]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: 2-Bromo-4-fluorobenzaldehyde
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• 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: EC1 cells; Esophagus; Homo sapiens (Human); CVCL_DC74
• In Vitro Model: HEEC cells; Esophagus; 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
• Mechanism Description: miroRNA-127-3p targets XRCC3 to enhance the chemosensitivity of esophageal cancer cells to a novel phenanthroline-dione derivative.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein XRCC3 (XRCC3) [36]

• Sensitive Disease: Esophageal cancer [ICD-11: 2B70.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: 2-Bromo-4-fluorobenzaldehyde
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• 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: EC1 cells; Esophagus; Homo sapiens (Human); CVCL_DC74
• In Vitro Model: HEEC cells; Esophagus; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miroRNA-127-3p targets XRCC3 to enhance the chemosensitivity of esophageal cancer cells to a novel phenanthroline-dione derivative.

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