Drug Information

Drug (ID: DG00153) and It's Reported Resistant Information

• Name: Temozolomide
• Synonyms: Methazolastone; Temodal; Temodar; Temozolamide; Temozolodida; Temozolomidum; Essex brand of temozolomide; Scheringbrand of temozolomide; Temozolodida [Spanish]; Temozolomidum [Latin]; M B 39831; MB 39831; Sch 52365; M & B 39831; M&B 39831; M-39831; Sch-52365; Schering-Plough brand of temozolomide; TMZ-Bioshuttle; Temodal (TN); Temodar (TN); Temozolomide [INN:BAN]; M&B-39831; Temozolomide (JAN/USAN/INN); 3,4-Dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide; 3,4-Dihydro-3-methyl-4-oxoimidazo(5,1-d)-as-tetrazine-8-carboxamide; 3-Methyl-4-oxo-3,4-dihydroimidazo(5,1-d)(1,2,3,5)tetrazine-8-carboxamide; 3-Methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetraazine-8-carboxamide; 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide; 3-methyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide; 8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one; TMZ
• Indication:
  In total 1 Indication(s)
  Brain cancer [ICD-11: 2A00]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (7 diseases)
  Brain cancer [ICD-11: 2A00]; [2]
  Chronic myeloid leukemia [ICD-11: 2A20]; [2]
  Glioblastoma [ICD-11: 2A00]; [6]
  Glioma [ICD-11: 2A00]; [4]
  Head and neck squamous cell carcinoma [ICD-11: 2D42]; [6]
  Lung adenocarcinoma [ICD-11: 2C25]; [4]
  Pituitary cancer [ICD-11: 2F37]; [11]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Brain cancer [ICD-11: 2A00]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (9 diseases)
  Brain glioma [ICD-11: 2A00]; [4]
  Colorectal cancer [ICD-11: 2B91]; [4]
  Gastric cancer [ICD-11: 2B72]; [5]
  Glioblastoma [ICD-11: 2A00]; [7]
  Glioma [ICD-11: 2A00]; [8]
  Neuroblastoma [ICD-11: 2A00]; [9]
  Non-small cell lung cancer [ICD-11: 2C25]; [10]
  Brain cancer [ICD-11: 2A00]; [12]
  Lung cancer [ICD-11: 2C25]; [13]
• Target: Human Deoxyribonucleic acid (hDNA); NOUNIPROTAC; [1]
• Formula: C6H6N6O2
• IsoSMILES: CN1C(=O)N2C=NC(=C2N=N1)C(=O)N
• InChI: 1S/C6H6N6O2/c1-11-6(14)12-2-8-3(4(7)13)5(12)9-10-11/h2H,1H3,(H2,7,13)
• InChIKey: BPEGJWRSRHCHSN-UHFFFAOYSA-N
• PubChem CID: 5394
• ChEBI ID: CHEBI:72564
• TTD Drug ID: D0C8EU
• DrugBank ID: DB00853

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [14]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.55E-01; Fold-change: -6.57E-02; Z-score: -1.43E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR138/BIM signaling pathway; Regulation; N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vitro Model: D247MG cells; Brain; Homo sapiens (Human); CVCL_1153
• In Vitro Model: LN-319 cells; Brain; Homo sapiens (Human); CVCL_3958
• In Vitro Model: LN-428 cells; Brain; Homo sapiens (Human); CVCL_3959
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [20]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.13E-14; Fold-change: 1.21E+00; Z-score: 1.64E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: MALAT1 decreased the sensitivity of resistant glioma cell lines to TMZ by upregulating ZEB1.

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.00E-01; Fold-change: 8.10E-03; Z-score: 1.48E-01
• 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: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: Transcription factor Sp1 (SP1) [24]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.59E-26; Fold-change: 7.80E-02; Z-score: 1.10E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST was inversely correlated with miR29c, positively correlated with PS1, positively related with MGMT. XIST can inhibit miR29c expression by directly binding to miR29c and subsequently up-regulate the expression of SP1 and MGMT to promote the chemoresistance of glioma cells to TMZ.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [23]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: White matter
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.65E-01; Fold-change: 4.99E-02; Z-score: 9.29E-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: For drugs that have evaded cytosolic mechanisms of drug resistance, the nucleus is equipped with the capacity to remove BCNU or temozolomide alkyl groups from the O6-position of guanine via a reaction catalyzed by MGMT. Repair occurs before cross-link formation and involves an irreversible stoichiometric covalent transfer of the O6-alkyl DNA adduct to a cysteine within the active site of MGMT, resulting in the inactivation and subsequent depletion of enzyme activity. MGMT-mediated repair is rapid, with a half-life of 35 hours. MGMT enzyme recovery occurs via de novo synthesis. In malignant glioma patients, MGMT overexpression has been associated with resistance to BCNU and similar alkylating agents and was an independent predictor of poor survival. MGMT is also thought to contribute to temozolomide resistance, which we did not detect in our study. This may be related to the in vitro pharmacokinetic differences between BCNU and temozolomide.

Key Molecule: CCN family member 1 (CYR61) [30]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.55E-58; Fold-change: 2.09E-01; Z-score: 1.72E+01
• 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: RAF/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of CYR61 increased the survival rate of U251/TMZ and U87/TMZ cells after TMZ treatment, while induction of miR-634 significantly suppressed the survival of U251/TMZ and U87/TMZ cells after TMZ treatment.

Key Molecule: Endoplasmin (HSP90B1) [31]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.64E-05; Fold-change: 1.87E-01; Z-score: 6.85E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: UPR signaling pathway; Activation; hsa0414)
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nu/nu athymic mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Transcripts for the ER chaperones GRP94 and GRP78 were upregulated in the U87MG and U87+EGFR gliomas, relative to normal mouse brain from healthy animals. Elevated levels of UPR transcription factors and ER chaperones correlated with poor patient prognosis; western blots of high grade gliomas and tissue microarray immunohistochemistry verified high expression of UPR players, especially GRP94, in high grade gliomas. Activation of the UPR signaling pathways is a prominent feature of glioma biology that leads to metabolic shifts and enhances chemoresistant features of gliomas.

Key Molecule: DNA repair protein XRCC4 (XRCC4) [33]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.31E-104; Fold-change: 1.22E-01; Z-score: 2.42E+01
• 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 viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Inhibiting miR-151a leads to increased XRCC4 levels, resulting in activated DNA repair and subsequent resistance to TMZ.

Key Molecule: Endoplasmic reticulum chaperone BiP (HSPA5) [31]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.68E-114; Fold-change: 1.16E-01; Z-score: 2.64E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: UPR signaling pathway; Activation; hsa0414)
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nu/nu athymic mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Transcripts for the ER chaperones GRP94 and GRP78 were upregulated in the U87MG and U87+EGFR gliomas, relative to normal mouse brain from healthy animals. Elevated levels of UPR transcription factors and ER chaperones correlated with poor patient prognosis; western blots of high grade gliomas and tissue microarray immunohistochemistry verified high expression of UPR players, especially GRP94, in high grade gliomas. Activation of the UPR signaling pathways is a prominent feature of glioma biology that leads to metabolic shifts and enhances chemoresistant features of gliomas.

Key Molecule: G1/S-specific cyclin-E1 (CCNE1) [34]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.46E-04; Fold-change: 1.12E-01; Z-score: 4.87E+00
• 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: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Hsa-miR-195 could negatively regulate the expression of CCNE1 in glioma and microRNA-195 reverses the resistance to temozolomide through targeting cyclin E1 in glioma cells.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [39]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.79E-15; Fold-change: -2.07E-02; Z-score: -7.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Activation; hsa04212
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN382 cells; Brain; Homo sapiens (Human); CVCL_3956
• In Vitro Model: SF295 cells; Brain; Homo sapiens (Human); CVCL_1690
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Up-regulation of miR-497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl-2. The silencing of miR-497 decreased the protein levels of IGF1R/IRS1 pathway-related proteins, that is, IGF1R, IRS1, mTOR, and Bcl-2.

Key Molecule: Paired box protein Pax-6 (PAX6) [41]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.73E-01; Fold-change: -2.68E-02; Z-score: -1.96E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Transwell assay; Transwell matrix penetration assay; MTT assay; BrdU incorporation assay
• Mechanism Description: miR223/PAX6 axis regulates glioblastoma stem cell proliferation and the chemo resistance to TMZ via inhibition of PI3k/Akt pathway.

Key Molecule: Programmed cell death protein 4 (PDCD4) [46]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.63E-10; Fold-change: -6.84E-02; Z-score: -6.22E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Ectopic overexpression of miR-497 promotes chemotherapy resistance in glioma cells by targeting PDCD4, a tumor suppressor that is involved in apoptosis. In contrast, the inhibition of miR-497 enhances apoptosis and increases the sensitivity of glioma cells to TMZ.

Key Molecule: Tumor suppressor candidate 3 (TUSC3) [47]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.98E-06; Fold-change: -7.25E-02; Z-score: -4.60E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: U87MG-res cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Immunofluorescence staining; Western blot analysis
• Experiment for Drug Resistance: Soft agar assay; MTT assay; Sphere formation assay
• Mechanism Description: microRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma.

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.31E-30; Fold-change: -1.07E-01; Z-score: -1.18E+01
• 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: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [29]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell cytotoxicity; Activation; hsa04650
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. CASC2 is downregulated in gliomas, resulting in increased miR193a-5p level and a decrease in mTOR expression, which further induces protective autophagy, leading to TMZ resistance.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [24]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST was inversely correlated with miR29c, positively correlated with PS1, positively related with MGMT. XIST can inhibit miR29c expression by directly binding to miR29c and subsequently up-regulate the expression of SP1 and MGMT to promote the chemoresistance of glioma cells to TMZ.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [39]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Activation; hsa04212
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN382 cells; Brain; Homo sapiens (Human); CVCL_3956
• In Vitro Model: SF295 cells; Brain; Homo sapiens (Human); CVCL_1690
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Up-regulation of miR-497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl-2. The silencing of miR-497 decreased the protein levels of IGF1R/IRS1 pathway-related proteins, that is, IGF1R, IRS1, mTOR, and Bcl-2.

Key Molecule: Growth protein 4 inhibitor (ING4) [54]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: N3 GBM cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell-cycle assay
• Mechanism Description: miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [55]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• 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: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The mechanism responsible for resistance of glioma cells to temozolomide was associated with miR-16-mediated downregulation of Bcl-2. miR-16 may function as an important modifier of the response of glioma cells to temozolomide.

Key Molecule: DNA mismatch repair protein Msh6 (MSH6) [65]

• Resistant Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: SSCP assay; Direct sequencing assay
• Mechanism Description: Prominent example of therapy-induced molecular alterations in gliomas which themselves ensue therapeutic consequences are MSH6 mutations in glioblastomas which arise during temozolomide chemotherapy and which are able to convey temozolomide resistance in affected tumors.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [66]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin/MGMT signaling pathway; Regulation; N.A.
• In Vitro Model: U251R cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.

Key Molecule: Taurine up-regulated 1 (TUG1) [3]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NEAT1/miR-454-3p/Connexin 43 signaling pathway; Regulation; N.A.
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [66]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin/MGMT signaling pathway; Regulation; N.A.
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U251R cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [3]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: NEAT1/miR-454-3p/Connexin 43 signaling pathway; Regulation; N.A.
• In Vivo Model: Normal brain tissues; Patient-derived primary GBM model; Patient-derived recurrent GBM model; Homo sapiens
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice.

Key Molecule: Catenin beta-1 (CTNNB1) [66]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Beta-catenin/MGMT signaling pathway; Regulation; N.A.
• In Vitro Model: U251R cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/beta-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated beta-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/beta-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and beta-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.

Key Molecule: Neat2 [3]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; .
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NEAT1/miR-454-3p/Connexin 43 signaling pathway; Regulation; N.A.
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The results showed that recurring gliomas displayed elevated levels of NEAT1 compared to primary gliomas. The suppression of NEAT1 led to a restoration of sensitivity in GBM cells to TMZ. NEAT1 functioned as a competitive endogenous RNA against miR-454-3p. Connexin 43 was identified as a miR-454-3p target. NEAT1 was found to regulate gap junctional intercellular communication by modulating Connexin 43, thereby impacting the response of GBM cells to TMZ chemotherapy. Downregulation of NEAT1 resulted in enhanced chemosensitivity to TMZ and extended the survival of mice.

Key Molecule: Dual specificity protein kinase TTK (TTK) [67]

• Resistant Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [17]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Malignant glioma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.18E-01; Fold-change: 2.37E-01; Z-score: 1.69E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [18]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.79E-03; Fold-change: -3.77E-01; Z-score: -3.50E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Upregulation of TUSC7,which acted by directly targeting and silencing expression of miR-10a gene, suppressed both TMZ resistance and expression of multidrug resistance protein 1 (MDR1) in U87TR cells,, and miR-10a mediated TUSC7-induced inhibition on TMZ resistance in U87TR cells.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [17]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.59E-117; Fold-change: 1.21E-01; Z-score: 2.56E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [17]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Glioblastoma tissue; N.A.
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Patient survival time
• Mechanism Description: In the chemosensitive MDR1-negative parental cell line k562 10 ug/ml temozolomide resulted in pronounced cell death with only 47.1% surviving 48 h compared with the control. In contrast, in the highly MDR1-expressing resistant subline k562-VP16, cell death was significantly lower after exposure to temozolomide with 73.4% surviving 48 h (P = 0.002). Addition of a nontoxic dose of the MDR1-modulator cyclosporine A (1 uM) to temozolomide resulted in a trend towards restoration of chemosensitivity in the resistant MDR1-expressing cell line.

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [23]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.43E-75; Fold-change: 9.33E-02; Z-score: 2.02E+01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: GSTP1 is the first major mechanism of resistance alkylator agents encounter after entering the cancer cell cytoplasm. GSTP1 acts to enzymatically conjugate glutathione to the reactive metabolites of BCNU. The mechanisms by which GSTP1 may be up-regulated in gliomas are under investigation. Constitutive expression is thought to be influenced by the proximal promoter factor Sp1, whereas increased expression levels may result from stabilization of GSTP1 mRNA. GSTP1 expression has been reported to be induced by drug exposure, indicating that it may play a role in acquired drug resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR) [1]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma multiforme
• The Studied Tissue: Brain
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.06E-05; Fold-change: 7.56E-01; Z-score: 4.51E+00
• 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: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [17]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma multiforme
• The Studied Tissue: Brain
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.56E-04; Fold-change: 2.67E+00; Z-score: 3.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: Tumor suppressor candidate 7 (TUSC7) [18]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma multiforme
• The Studied Tissue: Brain
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.84E-03; Fold-change: -1.08E+00; Z-score: -3.00E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Upregulation of TUSC7,which acted by directly targeting and silencing expression of miR-10a gene, suppressed both TMZ resistance and expression of multidrug resistance protein 1 (MDR1) in U87TR cells,, and miR-10a mediated TUSC7-induced inhibition on TMZ resistance in U87TR cells.

Key Molecule: hsa-miR-20b-3p [1]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• 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: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: hsa-miR-20b-3p [1]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• 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: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: Cancer susceptibility 2 (CASC2) [29], [32]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. CASC2 is downregulated in gliomas, resulting in increased miR193a-5p level and a decrease in mTOR expression, which further induces protective autophagy, leading to TMZ resistance.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [20], [53]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR203-TS signaling pathway; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: LncRNA MALAT1 inhibition re-sensitized TMZ resistant cells through up-regulating miR203 and down-regulating TS expression. MALAT1 decreased the sensitivity of resistant glioma cell lines to TMZ by upregulating ZEB1.

Key Molecule: hsa-mir-132 [47]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: U87MG-res cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Soft agar assay; MTT assay; Sphere formation assay
• Mechanism Description: microRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma.

Key Molecule: hsa-mir-29c [24]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; RIP assay; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR29c via SP1 and MGMT. XIST expression was up-regulated by miR29c inhibition while down-regulated by ectopic miR29, and XIST directly binds to miR29c to inhibit its expression, XIST and miR29c neatively regulates each other.

Key Molecule: X inactive specific transcript (XIST) [24]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST was inversely correlated with miR29c, positively correlated with PS1, positively related with MGMT. XIST can inhibit miR29c expression by directly binding to miR29c and subsequently up-regulate the expression of SP1 and MGMT to promote the chemoresistance of glioma cells to TMZ.

Key Molecule: hsa-mir-223 [41]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Transwell assay; Transwell matrix penetration assay; MTT assay; BrdU incorporation assay
• Mechanism Description: miR223/PAX6 axis regulates glioblastoma stem cell proliferation and the chemo resistance to TMZ via inhibition of PI3k/Akt pathway.

Key Molecule: hsa-mir-181a [32]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: LncRNA CASC2 interacts with miR181a to modulate glioma growth and resistance to TMZ through PTEN pathway.

Key Molecule: hsa-mir-497 [39]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Activation; hsa04212
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN382 cells; Brain; Homo sapiens (Human); CVCL_3956
• In Vitro Model: SF295 cells; Brain; Homo sapiens (Human); CVCL_1690
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Up-regulation of miR-497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl-2. The silencing of miR-497 decreased the protein levels of IGF1R/IRS1 pathway-related proteins, that is, IGF1R, IRS1, mTOR, and Bcl-2.

Key Molecule: hsa-mir-195 [34]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• 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: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Hsa-miR-195 could negatively regulate the expression of CCNE1 in glioma and microRNA-195 reverses the resistance to temozolomide through targeting cyclin E1 in glioma cells.

Key Molecule: hsa-mir-151a [33]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• 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 viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Inhibiting miR-151a leads to increased XRCC4 levels, resulting in activated DNA repair and subsequent resistance to TMZ.

Key Molecule: hsa-mir-101 [52]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expressiom; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [52]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: hsa-miR-634 [30]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: RAF/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of CYR61 increased the survival rate of U251/TMZ and U87/TMZ cells after TMZ treatment, while induction of miR-634 significantly suppressed the survival of U251/TMZ and U87/TMZ cells after TMZ treatment.

Key Molecule: hsa-mir-10a [18]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Upregulation of TUSC7,which acted by directly targeting and silencing expression of miR-10a gene, suppressed both TMZ resistance and expression of multidrug resistance protein 1 (MDR1) in U87TR cells,, and miR-10a mediated TUSC7-induced inhibition on TMZ resistance in U87TR cells.

Key Molecule: hsa-miR-423-5p [54]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: N3 GBM cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Cell-cycle assay
• Mechanism Description: miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas.

Key Molecule: hsa-mir-138 [14]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR138/BIM signaling pathway; Regulation; N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vitro Model: D247MG cells; Brain; Homo sapiens (Human); CVCL_1153
• In Vitro Model: LN-319 cells; Brain; Homo sapiens (Human); CVCL_3958
• In Vitro Model: LN-428 cells; Brain; Homo sapiens (Human); CVCL_3959
• In Vivo Model: BALB/c nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype.

Key Molecule: hsa-mir-16 [55]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• 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: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The mechanism responsible for resistance of glioma cells to temozolomide was associated with miR-16-mediated downregulation of Bcl-2. miR-16 may function as an important modifier of the response of glioma cells to temozolomide.

Key Molecule: hsa-mir-497 [46]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Ectopic overexpression of miR-497 promotes chemotherapy resistance in glioma cells by targeting PDCD4, a tumor suppressor that is involved in apoptosis. In contrast, the inhibition of miR-497 enhances apoptosis and increases the sensitivity of glioma cells to TMZ.

Key Molecule: hsa-mir-125b-2 [56]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Inhibition; hsa04210
• In Vitro Model: Human glioblastoma tissues and PRGMTTT samples; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-125b-2 is overexpressed in glioblastoma multiforme tissues and the corresponding stem cells (GBMSC); downregulation of miR-125b-2 expression in GBMSC could allow TMZ to induce GBMSC apoptosis. Additionally, the expression of the anti-apop-totic protein Bcl-2 was decreased after the TMZ+miR-125b-2 inhibitor treatment, while the expression of the proapoptotic protein Bax was increased. he induction of apoptosis in GBMSC is also associated with increased cytochrome c release from mitochondria, induction of Apaf-1, activation of caspase-3 and poly-ADP-ribose polymerase (PARP). miR-125b-2 overexpression might confer glioblastoma stem cells resistance to TMZ.

Key Molecule: hsa-mir-21 [12]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• 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: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: miR-21 could inhibit TMZ-induced apoptosis in U87MG cells, at least in part, by decreasing Bax/Bcl-2 ratio and caspase-3 activity.

Key Molecule: hsa-miR-455-3p [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-106b [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-10a-3p [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-455 [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-502 [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-584 [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-210 [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-193a [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-452 [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-503 [9]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: MiRNA microarray
• Experiment for Drug Resistance: Water-soluble tetrazolium salt (WST)-based assay
• Mechanism Description: We then performed a comprehensive analysis of miRNA expressions in U251R and parental cells using miRNA microarrays. miR-195, miR-455-3p and miR-10a* were the three most up-regulated miRNAs in the resistant cells. Thirteen miRNAs were overexpressed (>2.0-fold) and two were underexpressed (<0.5-fold) in U251R cells compared to U251Wt cells. In addition, using in silico analysis combined with cDNA microarray experiment, we present possible mRNA targets of these miRNAs.

Key Molecule: hsa-miR-125b-1 [56]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Caspase-3 activity assay
• Mechanism Description: miR-125b-2 is overexpressed in glioblastoma multiforme tissues and the corresponding stem cells (GBMSC); downregulation of miR-125b-2 expression in GBMSC could allow TMZ to induce GBMSC apoptosis. Additionally, the expression of the anti-apop totic protein Bcl-2 was decreased after the TMZ+miR-125b-2 inhibitor treatment, while the expression of the proapoptotic protein Bax was increased. Further research demonstrated that the induction of apoptosis in GBMSC is also associated with increased cytochrome c release from mitochondria, induction of Apaf-1, activation of caspase-3 and poly-ADP-ribose polymerase(PARP). Taken together, these results suggest that miR-125b-2 overexpression might confer glioblastoma stem cells resistance to TMZ.

Key Molecule: hsa-miR-16-1 [57]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: LN382 cells; Brain; Homo sapiens (Human); CVCL_3956
• In Vitro Model: AM-38 cells; Brain; Homo sapiens (Human); CVCL_1070
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR; Western blot
• Experiment for Drug Resistance: CCK-8 assay; Apoptosis assay
• Mechanism Description: In conclusion, MiR-16 mediated temozolomide-resistance in glioma cells by modulation of apoptosis via targeting Bcl-2, which suggesting that miR-16 and Bcl-2 would be potential therapeutic targets for glioma therapy.

Key Molecule: DLX6-AS1 [6]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Mechanism Description: Li et al. found that DLX6-AS1 expression was dramatically upregulated in glioma cells and tissues. Additionally, DLX6-AS1 overexpression was associated with a poorer prognosis for glioma patients, according to the clinical correlation.

Key Molecule: LINC00942 [4]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: STAT3/P300 axis; Regulation; N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: PCR; RT-qPCR; High-Throughput Sequencing; RNA Pull-Down; Western Blot; Immunofluorescence; Chromatin Immunoprecipitation; Immunohistochemistry
• Experiment for Drug Resistance: CCK-8 Assay; EdU Assay; Flow Cytometry
• Mechanism Description: Linc00942 strongly promotes SOX9 expression by interacting with TPI1 and PKM2 is found, thereby driving self-renewal and TMZ resistance in GBM cells.

Key Molecule: KCNQ1OT1 [4]

• Resistant Disease: Glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Dual?Luciferase Assay; Western Blot; qRT?PCR; Immunohistochemical; Immunofluorescence
• Experiment for Drug Resistance: Clonogenicity Assay; Apoptosis Analysis; MTT Assay
• Mechanism Description: The present study demonstrated that the lncRNA KCNQ1OT1 increased in TMZ-resistant glioma cells compared to the TMZ-sensitive cells. The introduction of KCNQ1OT1 promoted cell viability, clonogenicity, and rhodamine 123 efflux while hampering TMZ-induced apoptosis. Moreover, KCNQ1OT1 directly sponged miR-761, which decreased in TMZ-resistant sublines. The overexpression of miR-761 attenuated cell viability and clonogenicity, while triggering apoptosis and rhodamine 123 accumulation post-TMZ exposure, leading to a response to TMZ. The interaction between miR-761 and 3'-untranslated region of PIM1 attenuated PIM1-mediated signaling cascades. Furthermore, the knockdown of KCNQ1OT1 augmented the TMZ-induced tumor regression in TMZ-resistant U251 mouse models. Briefly, the present study evaluated that KCNQ1OT1 conferred TMZ resistance by releasing PIM1 expression from miR-761, resulting in the upregulation of PIM-mediated MDR1, c-Myc, and Survivin. The present findings demonstrated that the interplay of KCNQ1OT1: miR-761: PIM1 regulated chemoresistance in gliomas and provided a promising therapeutic target for TMZ-resistant glioma patients.

Key Molecule: LINC01564 [4]

• Resistant Disease: Glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western blot; RNA-binding protein immunoprecipitation (RIP) assay; Luciferase reporter assay; Immunoprecipitation; RNA pulldown assay
• Experiment for Drug Resistance: CCK8 assay; EdU assay; Flow cytometry; Iron detection assay
• Mechanism Description: LINC01564 Promotes the TMZ Resistance of Glioma Cells by Upregulating NFE2L2 Expression to Inhibit Ferroptosis.

Key Molecule: LINC00601 [6]

• Resistant Disease: Glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p-STAT3 signaling pathway; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Cell migration assay; Cell invasion assay
• Mechanism Description: LINC00601, which facilitates glioma progression by modulating the p-STAT3 signaling pathway, could serve as a potential molecular target for glioma therapy.

Key Molecule: HOXA-AS2 [4]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR-302a-3p/IGF1 Axis; Regulation; N.A.
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Glioblastoma patients; Homo sapiens
• Experiment for Molecule Alteration: RNA Immunoprecipitation; qPCR
• Experiment for Drug Resistance: Viability assay; Chemosensitivity assay
• Mechanism Description: TMZ-resistant GBM patients and cell lines exhibited increased HOXA-AS2 expression that was correlated with worse overall survival. Knocking down HOXA-AS2 increased the sensitivity of resistant GBM cells to TMZ. miR-302a-3p was identified as a HOXA-AS2 target confirmed through luciferase reporter assays and rescue experiments, and IGF1 was further identified as a confirmed miR-302a-3p target. In addition, HOXA-AS2 knockdown resulted in a corresponding drop in IGF1 expression consistent with indirect regulation mediated by miR-302a-3p. Conclusion. In summary, these results highlight the role of HOXA-AS2 as a driver of TMZ resistance in GBM through its ability to regulate the miR-302a-3p/IGF1 signaling axis, highlighting this pathway as a promising target for the diagnosis, therapeutic sensitization, and/or treatment of affected patients.

Key Molecule: DLGAP1-AS1 [4]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our conclusion suggested that DLGAP1-AS1 may be a potential prognosis biomarker and facilitated the occurrence and development of glioma via ATG4A in GBM.

Key Molecule: LINC01198 [8]

• Resistant Disease: Glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; RNA immunoprecipitation; RNA pulldown assay; Western blotting
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistically, NEDD4-1 (neural precursor cell expressed, developmentally downregulated 4, E3 ubiquitin protein ligase) and phosphatase and tensin homolog (PTEN) were recruited by LINC01198, which functioned as a scaffold. Moreover, we showed that LINC01198 exerted its oncogenic activities by enhancing the NEDD4-1-dependent repression of PTEN.

Key Molecule: SOX2-OT [4]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Wnt5a/beta-catenin signaling pathway; Regulation; N.A.
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Glioblastoma patients; Nude mouse xenograft model; Homo sapiens
• Experiment for Molecule Alteration: RT-qPCR; Western blot; Immunohistochemistry staining; RNA pulldown assay; RNA immunoprecipitation assay; MeRIP-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric
• Mechanism Description: Mechanistically, further investigation revealed that SOX2OT recruited ALKBH5, which binds with SOX2, demethylating the SOX2 transcript, leading to enhanced SOX2 expression. Together, these results demonstrated that LncRNA SOX2OT inhibited cell apoptosis, promoted cell proliferation, and TMZ resistance by upregulating SOX2 expression, which activated the Wnt5a/beta-catenin signaling pathway.

Key Molecule: LINC00461 [4]

• Resistant Disease: Glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR-216a/AQP4 axis; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Glioma patients; Nude mouse xenograft model; Homo sapiens
• Experiment for Molecule Alteration: RT-qPCR; Western blotting; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Transwell assay
• Mechanism Description: In conclusion, LINC00461 knockdown inhibits glioma cell proliferation, migration, invasion, and TMZ resistance through miR-216a/AQP4 axis, suggesting LINC00461 as an oncogene in glioma progression.

Key Molecule: HAS2-AS1 [4]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western Blot; Dual-Luciferase Reporter Assays; Immunohistochemistry
• Experiment for Drug Resistance: CCK8 assay; Colony Formation Assay
• Mechanism Description: We conclude that lncRNA HAS2-AS1 promotes proliferation by functioning as a miR-137 decoy to increase LSD1 levels and thus might be a possible biomarker for GBM.

Key Molecule: IGF2-AS [5]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K signaling axis; Regulation; N.A.
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR; Western blot; Immunohistochemistry
• Experiment for Drug Resistance: Cell viability assays; PI apoptosis assay
• Mechanism Description: IGF2 associated PI3K signaling shapes temozolomide sensitivity in glioblastoma

Key Molecule: UCA1 [4]

• Resistant Disease: Glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: UCA1/miR-182-5p/MGMT axis; Regulation; N.A.
• In Vitro Model: HEB cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vivo Model: Glioma patients; Nude mouse xenograft model; Homo sapiens
• Experiment for Molecule Alteration: RT-PCR; Immunoblotting; Dual-luciferase reporter gene assay
• Experiment for Drug Resistance: Histological analyses; MTT assay; Flow cytometry
• Mechanism Description: UCA1 knockdown in glioma cells enhanced the sensitivity to TMZ.miR-182-5p could simultaneously target lncRNA UCA1 and MGMT 3'UTR.lncRNA UCA1/miR-182-5p/MGMT axis modulates glioma cell sensitivity to TMZ via MGMT-related DNA damage pathways.

Key Molecule: hsa-miR-193b-3p [7]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ras-MAPK signalling pathway; Regulation; N.A.
• Cell Pathway Regulation: PI3K-AKT signalling pathway; Regulation; N.A.
• Cell Pathway Regulation: Wnt signalling pathway; Regulation; N.A.
• Experiment for Molecule Alteration: Differential expression analysis; Functional and pathway enrichment analysis; Construction of protein-protein interaction (PPI) networks and screening for key genes
• Mechanism Description: Finally, another upregulated miRNA is hsa-miR-193b-3p, and although higher expression of hsa-miR-193b-3p has been found in glioma and colorectal cancer, it is seen to be a tumor suppressor, and in our study, hsa-miR-193b was found to be upregulated and significantly enriched in pathways effective on both cell viability and proliferation.

Key Molecule: hsa-miR-155 [6]

• Resistant Disease: Brain glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Cytotoxicity assay; Apoptosis assay; Cell cycle assay
• Mechanism Description: Combining temozolomide and anti-miR- 155 - 5p inhibits DNA synthesis by causing G2 phase arrest. mRNAs targeted by miR- 155 - 5p and significantly down-regulated in glioblastoma included GABRA1, GABRB2, SCN1A, GRIN2A, and SGIP1. By survival analysis, low expression of SCN1A was associated with poor prognosis (p < 0.05; HR = 0.7), highlighting its potential prognostic role. The combination of temozolomide treatment with suppression of miR- 155 - 5p may provide a more effective and side-effect minimized brain cancer treatment strategy by reducing resistance.

Key Molecule: SNAI3-AS1 [4]

• Resistant Disease: Glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SNAI3-AS1/SND1/Nrf2 signalling axis; Regulation; N.A.
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: Glioma patients; Nude mouse xenograft model; Homo sapiens
• Experiment for Molecule Alteration: RT-qPCR; Bisulfite sequencing PCR; Western blotting; RNA pull-down; RIP assays; Immunofluorescence; Immunohistochemistry; Dual-luciferase reporter assays; mRNA stability assays
• Experiment for Drug Resistance: Cell viability assays;Ccolony formation assays; EdU assays; Cell migration assays; Cell invasion assays; Cell cycle assays; Iron assays; Lipid ROS assays
• Mechanism Description: We found that ferroptosis inducer erastin downregulates SNAI3-AS1 expression in glioma by increasing the DNA methylation level of SNAI3-AS1 promoter. SNAI3-AS1 functions as a tumor suppressor in glioma. Importantly, SNAI3-AS1 enhances the anti-tumor activity of erastin by promoting ferroptosis both in vitro and in vivo. Mechanistically, SNAI3-AS1 competitively binds to SND1 and perturbs the m6A-dependent recognition of Nrf2 mRNA 3'UTR by SND1, thereby reducing the mRNA stability of Nrf2. Rescue experiments confirmed that SND1 overexpression and silence can rescue the gain- and loss-of-function ferroptotic phenotypes of SNAI3-AS1, respectively.

Key Molecule: TRPM2-AS [58]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: Glioblastoma patients; Homo sapiens
• Experiment for Molecule Alteration: Western blot
• Experiment for Drug Resistance: Cell proliferation assay; Neurite outgrowth assay
• Mechanism Description: Hypoxia promotes temozolomide resistance in glioblastoma cells via ROS- mediated up-regulation of TRPM2

Key Molecule: LUCAT1 [6]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Interaction network and functional enrichment analysis; Differential expression analysis
• Experiment for Drug Resistance: Data analysis
• Mechanism Description: Of the 34 lncRNAs, LUCAT1, TCL6, MIR4458HG and LINC00114 may play a vital role in TMZ chemotherapy resistance of GBM cells. Yansheng gao et al. revealed that LUCAT1 could act as a oncogenic lncRNA and promote glioma tumorigenesis via regulating miR-375.

Key Molecule: MAGI2-AS3 [4]

• Resistant Disease: Brain glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT pathway; Regulation; N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: MAGI2-AS3 was expressed at low levels in TMZ-resistant GBM cells relative to that in their parental cells. MAGI2-AS3 re-expression alleviated TMZ resistance in TMZ-resistant GBM cells. MAGI2-AS3 overexpression also accelerated TMZ-induced apoptosis and G2/M phase arrest. Mechanistically, MAGI2-AS3 overexpression reduced MDR1 and ABCG2 expression and inhibited the Akt pathway, whereas Akt overexpression abrogated the reduction in MDR1 and ABCG2 expression induced by MAGI2-AS3. Moreover, activation of the Akt pathway inhibited the effects of MAGI2-AS3 on TMZ resistance. MAGI2-AS3 inhibited tumor growth and enhanced the suppressive effect of TMZ on glioma tumorigenesis in vivo. In conclusion, MAGI2-AS3 reverses TMZ resistance in glioma cells by inactivating the Akt pathway.

Key Molecule: DRAIC [4]

• Resistant Disease: Brain glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Autophagy; Regulation; N.A.
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-qPCR
• Mechanism Description: DRAIC activates AMP-activated protein kinase (AMPK) by downregulating the NF-kappaB target gene GLUT1, and thus represses mTOR, leading to downstream effects, such as a decrease in protein translation and increase in autophagy. DRAIC, therefore, has an effect on multiple signal transduction pathways that are important for oncogenesis, namely, the NF-kappaB pathway and AMPK-mTOR-S6K/ULK1 pathway. The regulation of NF-kappaB, protein translation and autophagy by the same lncRNA explains the tumor-suppressive role of DRAIC in different cancers and reinforces the importance of lncRNAs as emerging regulators of signal transduction pathways.

Key Molecule: MSC-AS1 [4]

• Resistant Disease: Brain glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT pathway; Regulation; N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MSC-AS1 was up-regulated in TMZ-resistant glioma tissues and cells, and glioma patients with high MSC-AS1 expression tend to have lower overall survival rate. MSC-AS1 suppression reduced the IC50 value of TMZ and proliferation, promoted apoptosis and TMZ sensitivity, and affected PI3K/Akt pathway in TMZ-resistant glioma cells. MSC-AS1 acted as miR-373-3p sponge, and miR-373-3p directly targeted CPEB4. Silencing miR-373-3p reversed the promoting effect of MSC-AS1 or CPEB4 knockdown on TMZ sensitivity. Furthermore, MSC-AS1 knockdown inhibited TMZ-resistant glioma growth in vivo by regulating miR-373-3p/CPEB4 axis through PI3K/Akt pathway. Collectively, MSC-AS1 knockdown suppressed cell growth and the chemoresistance of glioma cells to TMZ by regulating miR-373-3p/CPEB4 axis in vitro and in vivo through activating PI3K/Akt pathway.

Key Molecule: PSMG3-AS1 [4]

• Resistant Disease: Brain glioma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293T cells; Kindey; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Here we show that the long noncoding RNA (lncRNA) PSMG3-AS1 is significantly upregulated in GBM and its expression correlates with the grade of glioma, with the highest level observed in GBM (Grade IV glioma). We also demonstrated that PSMG3-AS1 mediates the resistance of GBM to TMZ, as knockdown of PSMG3-AS1 remarkably increased the sensitivity whereas overexpression of PSMG3-AS1 in sensitive GBM cell line induced a resistance phenotype to TMZ. Mechanistically, PSMG3-AS1 directly binds to c-Myc and thus stabilizes c-Myc in the nucleus to promote the survival of GBM cells under treatment of TMZ.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: SBF2 antisense RNA 1 (SBF2-AS1) [26]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma multiforme
• The Studied Tissue: Brain
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.14E-12; Fold-change: 6.90E-01; Z-score: 7.48E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB/XIAP signaling pathway; Activation; hsa04218
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Subcutaneous and orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Exosomal SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells.

Key Molecule: Vimentin (VIM) [28]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.64E-132; Fold-change: 2.85E-01; Z-score: 2.89E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• Experiment for Molecule Alteration: Western blot analysis; RNAi assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Silencing of H19 decreases chemoresistance through suppressing EMT via the Wnt/beta-Catenin pathway.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [28]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.67E-109; Fold-change: 1.73E-01; Z-score: 2.47E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• Experiment for Molecule Alteration: Western blot analysis; RNAi assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Silencing of H19 decreases chemoresistance through suppressing EMT via the Wnt/beta-Catenin pathway.

Key Molecule: hsa-miR-151a-3p [26]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• Cell Pathway Regulation: miR151a-3p/XRCC4 signaling pathway; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Subcutaneous and orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: RIP experiments; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Exosomal SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [28]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• 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: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Silencing of H19 decreases chemoresistance through suppressing EMT via the Wnt/beta-Catenin pathway.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: X-ray repair cross-complementing protein 1 (XRCC1) [59]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0]
• Molecule Alteration: Lactylation; K247
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Patients with GBM; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Survival after radiochemotherapy assay
• Mechanism Description: ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs

Key Molecule: Sponging microRNAs [60]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse glioma [ICD-11: 2A00.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: TMZ-resistant patients; Homo Sapiens
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Overall survival assay (OS)
• Mechanism Description: Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.

Key Molecule: Activating transcription factor 4 (ATF4) [61]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNT-22 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.

Key Molecule: Histone H3 [62]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Lactylation; H3K9la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TBD0220TR cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Lactylation is upregulated in recurrent glioblastoma (GBM) tissues and temozolomide (TMZ)-resistant cells, mainly concentrated in histone H3K9. H3K9 lactylation activates LUC7L2 transcription. LUC7L2 mediates MLH1 intron 7 retention to reduce MLH1 expression, thereby inhibit mismatch repair (MMR), ultimately leading to TMZ resistance.

Key Molecule: Gag-Pol polyprotein (HIV2 PR) [63]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: 8-week-old CAnN.Cg-Foxn1nu/CrlBltw (BALB/c nude) male mice, with U87MG-R cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay; Tumor weight assay
• Mechanism Description: Sp1-regulated PGE2 production activates FAO and TCA cycle in mitochondria, through EP1 and EP3 receptors, resulting in TMZ resistance in GBM. These results will provide us a new strategy to attenuate drug resistance or to re-sensitize recurred GBM.

Key Molecule: Down syndrome critical region 3 (DSCR3) [64]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice, with shDSCR3 or shNC U87 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: DSCR3 is upregulated in MGMT-deficient GBM cells during TMZ treatment. Both DSCR3 and SLC38A1 were highly expressed in recurrent GBM patients. Silencing DSCR3 or SLC38A1 expression can increase TMZ sensitivity in MGMT-deficient GBM cells. Combination of proteomics and in vitro experiments show that DSCR3 directly binds internalized SLC38A1 to mediate its sorting into recycling pathway, which maintains the abundance on plasma membrane and enhances uptake of glutamine in MGMT-deficient GBM cells.

Key Molecule: Sponging microRNAs [60]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse glioma [ICD-11: 2A00.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.

Key Molecule: Sponging microRNAs [60]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Diffuse glioma [ICD-11: 2A00.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: U251 cell xenograft model, U251/TR-sh-NC EXO; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Exosomal circ_0072083 promoted TMZ resistance via increasing NANOG via regulating miR-1252-5p-mediated degradation and demethylation in glioma.

Key Molecule: X-ray repair cross-complementing protein 1 (XRCC1) [59]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Aldh1a3-overexpressing glioblastoma [ICD-11: 2A00.0]
• Molecule Alteration: Lactylation; K247
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Rescue cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ALDH1A3-mediated tetramerization of PKM2 induces glycometabolic reprogramming in GSCs. Accumulation of lactate increases the lactylation of the K247 site on XRCC1. The lactylation of XRCC1 improves DNA repair via its increased nuclear localization. By blocking PKM2, D34-919 restores sensitivity to chemoradiotherapy for GBMs

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.79E-03; Fold-change: -3.77E-01; Z-score: -3.50E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Glioblastoma tissue; N.A.
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Patient survival time
• Mechanism Description: In the chemosensitive MDR1-negative parental cell line k562 10 ug/ml temozolomide resulted in pronounced cell death with only 47.1% surviving 48 h compared with the control. In contrast, in the highly MDR1-expressing resistant subline k562-VP16, cell death was significantly lower after exposure to temozolomide with 73.4% surviving 48 h (P = 0.002). Addition of a nontoxic dose of the MDR1-modulator cyclosporine A (1 uM) to temozolomide resulted in a trend towards restoration of chemosensitivity in the resistant MDR1-expressing cell line.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Potassium voltage-gated channel subfamily H member 1 (KCNH1) [15]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.05E-07; Fold-change: -1.72E+00; Z-score: -1.27E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Key Molecule: Ras-related protein Rap-1b (RAP1B) [16]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.37E-09; Fold-change: -3.47E-01; Z-score: -7.90E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Expression of Rap1B is negatively regulated by miR-128 and miR-149. TMZ inhibits Rap1B expression by upregulating miR-128 and miR-149. miR-128 and miR-149 suppress cell proliferation and invasion, and alter cytoskeletal remodeling by affecting Rap1B-associated small GTPase. miR-128 and miR-149 increase the chemosensitivity of TMZ in glioblastoma cells.

Key Molecule: Aurora kinase A (AURKA) [19]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.24E-03; Fold-change: -1.17E+00; Z-score: -4.08E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• In Vitro Model: M059k cells; Brain; Homo sapiens (Human); CVCL_0401
• In Vitro Model: U-87 MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 MG cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR124 suppresses glioblastoma growth and potentiates chemosensitivity by inhibiting AURkA. Re-expression of AURkA rescued miR124-mediated growth suppression.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [21]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: White matter
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.60E-02; Fold-change: 9.83E-02; Z-score: 2.14E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U373-MG; Brain; Homo sapiens (Human); CVCL_2219
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Celltiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: ATG7 is a potential target for miR-17, and this miRNA could negatively regulate ATG7 expression, resulting in a modulation of the autophagic status in T98G glioblastoma cells, the autophagy activation by anti-miR-17 resulted in a decrease of the threshold resistance at temozolomide doses in T98G cells.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [22]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.21E-136; Fold-change: 9.39E-02; Z-score: 3.00E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell formation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Inhibition of microRNA-299-5p sensitizes glioblastoma cells to temozolomide via upregulating GOLPH3 and inactivating the MAPk/ERk signaling pathway.

Key Molecule: E3 SUMO-protein ligase PIAS3 (PIAS3) [25]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.18E-47; Fold-change: 7.14E-02; Z-score: 1.52E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: GSCs cells; Brain; 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: Transwell invasion assay
• Mechanism Description: Inhibition of miR-125b expression may enhance sensitivity of GSCs to temozolomide by targeting PIAS3 on cell invasion.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [29]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.18E-01; Fold-change: 2.19E-03; Z-score: 2.34E-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. mTOR or CASC2 overexpression or miR193a-5p inhibition remarkably reduced autophagy-related proteins expression.

Key Molecule: Phosphatase and tensin homolog (PTEN) [32]

• Sensitive Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.13E-109; Fold-change: 1.46E-01; Z-score: 2.48E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: CASC2 up-regulated PTEN protein and down-regulated p-AkT protein through regulating miR181a, and the effect of CASC2 on PTEN and p-AkT could be partially restored by miR181a.

Key Molecule: Transcription factor E2F1 (E2F1) [35]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.94E-01; Fold-change: -2.14E-03; Z-score: -5.34E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of miR-196b increased glioma cell sensitivity to TMZ and E2F1 decreased following transfection with miR-196b inhibitors.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [36], [37]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.60E-01; Fold-change: -6.55E-03; Z-score: -9.16E-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; TMZ cytotoxicity assay; gamma -H2AX foci formation assay
• Mechanism Description: miR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [38]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.12E-01; Fold-change: -6.98E-03; Z-score: -1.59E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U87 GSCs; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-23b overexpression sensitized U87 glioma stem cells to TMZ-induced growth inhibition. And miR-23b had a synergistically suppressive effect on the expression of HMGA2 with TMZ in U87 GSCs.

Key Molecule: TNF receptor-associated factor 6 (TRAF6) [40]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.53E-01; Fold-change: -2.62E-02; Z-score: -2.33E-01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/NF-kappaB signaling pathway; Inhibition; hsa05135
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 146b 5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6. Overexpression of miR 146b 5p or TRAF6 knockdown significantly decreased the level of p AkT and p p65.

Key Molecule: Ras-related protein Rap-1b (RAP1B) [42]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: White matter
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.81E-03; Fold-change: -2.95E-02; Z-score: -3.38E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ras-associated protein 1 (Rap1), a growth regulatory protein, belongs to a member of RAS-like small GTP-binding protein superfamily. Rap1 regulates several basic cellular functions: migration, adhesion and growth. TMZ can inhibit the Rap1B expression to exert its cell killing by upregulating miR-181a/b/c/d subunits; conversely, each miR-181a/b/c/d subunit enhanced the chemosensitivity of TMZ in glioblastoma.

Key Molecule: Transcription factor Sp1 (SP1) [43]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.21E-02; Fold-change: -3.62E-02; Z-score: -1.96E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Ectopic expression of miR-29c increased TMZ sensitivity by inhibiting cell growth and promoting apoptosis in U251/TR cells.

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [45]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.25E-16; Fold-change: -6.07E-02; Z-score: -8.46E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: microRNA-101 reverses temozolomide resistance by inhibition of GSk3beta in glioblastoma.

Key Molecule: Transcription factor SOX-2 (SOX2) [48]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.12E-04; Fold-change: -1.08E-01; Z-score: -3.80E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: miR-126-3p sensitizes glioblastoma cells to temozolomide by inactivating Wnt/beta-catenin signaling via targeting SOX2.

Key Molecule: MAPK/ERK kinase 1 (MEK1) [49]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Brain cancer
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.08E-99; Fold-change: -1.64E-01; Z-score: -2.63E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-181b independently predicted chemoresponse to temozolomide and enhanced temozolomide sensitivity via MEk1 downregulation.

Key Molecule: Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) [50]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.91E-03; Fold-change: -2.09E-01; Z-score: -3.84E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: A novel mechanism independent of TP53 and MGMT by which oncogenic miR-125b confers TMZ resistance by targeting TNFAIP3 and NkIRAS2. GBM cells overexpressing miR-125b showed increased NF-kB activity and upregulation of anti-apoptotic and cell cycle genes. This was significantly associated with resistance of GBM cells to TNFalpha- and TNF-related inducing ligand-induced apoptosis as well as resistance to TMZ. Conversely, overexpression of anti-miR-125b resulted in cell cycle arrest, increased apoptosis and increased sensitivity to TMZ, indicating that endogenous miR-125b is sufficient to control these processes. GBM cells overexpressing TNFAIP3 and NkIRAS2 were refractory to miR-125b-induced apoptosis resistance as well as TMZ resistance, indicating that both genes are relevant targets of miR-125b.

Key Molecule: Epidermal growth factor receptor (EGFR) [51]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Neuroectodermal tumor
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.84E-08; Fold-change: -2.34E-01; Z-score: -1.06E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Dynamin-3 (DNM3) [27]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: Brainstem tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.87E-01; Fold-change: 3.77E-02; Z-score: 7.53E-01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vitro Model: HEB cells; Brain; 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: CCK8 assay; Transwell matrigel invasion assay; Scratch wound assay
• Mechanism Description: Exosomal miR221 targets DNM3 to induce tumor progression and temozolomide resistance in glioma. DNM3 is the target of miR221 and overexpression of DNM3 could reverse the miR221's tumour-promoting effect.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 2 (CASC2) [29]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma multiforme
• The Studied Tissue: Brain
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.59E-07; Fold-change: -3.83E-01; Z-score: -5.40E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: CASC2 negatively regulates miR193a-5p expression by direct interaction in glioma cells. Overexpression of CASC2 or inhibition of miR193a-5p reduced TMZ-induced autophagy via mTOR upregulation, which makes the glioma cells become sensitive to TMZ cytotoxicity.

Key Molecule: X inactive specific transcript (XIST) [24]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma multiforme
• The Studied Tissue: Brain
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.93E-26; Fold-change: -1.80E+00; Z-score: -1.10E+01
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR29c via SP1 and MGMT. XIST/miR29c axis regulated glioma cell chemoresistance to TMZ through RNA mismatch repair pathway. XIST expression was up-regulated by miR29c inhibition while down-regulated by ectopic miR29, and XIST directly binds to miR29c to inhibit its expression, XIST and miR29c neatively regulates each other.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [52]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioblastoma multiforme
• The Studied Tissue: Brain
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.44E-13; Fold-change: -2.24E+00; Z-score: -7.32E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: hsa-miR-126-3p [48]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: miR-126-3p sensitizes glioblastoma cells to temozolomide by inactivating Wnt/beta-catenin signaling via targeting SOX2.

Key Molecule: hsa-mir-23b [38]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U87 GSCs; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-23b overexpression sensitized U87 glioma stem cells to TMZ-induced growth inhibition. And miR-23b had a synergistically suppressive effect on the expression of HMGA2 with TMZ in U87 GSCs.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [71]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87-luc2; Brain; Homo sapiens (Human); CVCL_5J12
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: XTT assay; CellTiter-Glo Luminescent Cell Viability Assay
• Mechanism Description: Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide.

Key Molecule: hsa-miR-193a-5p [29]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. mTOR or CASC2 overexpression or miR193a-5p inhibition remarkably reduced autophagy-related proteins expression.

Key Molecule: hsa-miR-146b-5p [40]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/NF-kappaB signaling pathway; Inhibition; hsa05135
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 146b 5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6. Overexpression of miR 146b 5p or TRAF6 knockdown significantly decreased the level of p AkT and p p65.

Key Molecule: hsa-mir-29c [24]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; RIP assay; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR29c via SP1 and MGMT. XIST/miR29c axis regulated glioma cell chemoresistance to TMZ through RNA mismatch repair pathway. XIST expression was up-regulated by miR29c inhibition while down-regulated by ectopic miR29, and XIST directly binds to miR29c to inhibit its expression, XIST and miR29c neatively regulates each other.

Key Molecule: hsa-mir-181 [51]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor.

Key Molecule: hsa-miR-198 [37]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: miR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT.

Key Molecule: hsa-mir-124 [19]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• In Vitro Model: M059k cells; Brain; Homo sapiens (Human); CVCL_0401
• In Vitro Model: U-87 MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 MG cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR124 suppresses glioblastoma growth and potentiates chemosensitivity by inhibiting AURkA. Re-expression of AURkA rescued miR124-mediated growth suppression.

Key Molecule: hsa-mir-203 [53]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR203-TS signaling pathway; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR203 re-sensitizes TMZ resistant cells through directly targeting TS.

Key Molecule: Cancer susceptibility 2 (CASC2) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN signaling pathway; Activation; hsa05235
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: LncRNA CASC2 interacts with miR181a to modulate glioma growth and resistance to TMZ through PTEN pathway.

Drug Sensitive Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: MEG3 [68]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT; Regulation; N.A.
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MEG3 was then overexpressed by ligating to a lentiviral vector. Overexpressed MEG3 inhibited the proliferation of U-251 cells, and restrained the expression of proliferation marker proteins Ki67 and proliferating cell nuclear antigen (PCNA). However, cell apoptosis rate of U-251 cells and the expression of apoptosis marker proteins (caspase-3 and caspase-9) were elevated by MEG3. Furthermore, miR-93 was predicted a direct target of lncRNA-MEG3 by bioinformatics analysis. Overexpressed MEG3 counteracted the role of miR-93 in facilitating proliferation and inhibiting apoptosis in U-251 cells. Moreover, MEG3 restained the activation of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway by reducing cytomembrane translocation of AKT.

Key Molecule: hsa-miR-211 [69]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Intrinsic mitochondrial/Caspase-9/3-mediated apoptotic pathway; Regulation; N.A.
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Glioblastoma patient tumour model; Homo sapiens
• Experiment for Molecule Alteration: Immunoblotting; RT-PCR; Immunohistochemistry
• Experiment for Drug Resistance: Fluorescence-activated; TUNEL assay; Apoptotic DNA fragmentation analysis
• Mechanism Description: Furthermore, we found that miR-211 suppression in GBM involves aberrant methylation-mediated epigenetic silencing of the miR-211 promoter. Indeed, we observed a highly significant inverse correlation between miR-211 expression and MMP-9 protein levels, which is indicative of post-transcriptional control of gene expression. Additionally, shRNA specific for MMP-9 (pM) promoted miR-211 expression via demethylation of miR-211 promoter-associated CpG islands (-140 to +56). In independent experiments, we confirmed that miR-211 overexpression and pM treatments led to the activation of the intrinsic mitochondrial/Caspase-9/3-mediated apoptotic pathway in both glioma cells and cancer stem cells (CSC). We also investigated whether miR-211 is involved in the regulation of MMP-9 and thus plays a functional role in GBM. We found an acute inhibitory effect of miR-211 on glioma cell invasion and migration via suppression of MMP-9. Given the insensitivity of some GBMs to radiation and chemotherapy (temozolomide) along with the hypothesis that glioma CSC cause resistance to therapy, our study indicates that miR-211 or pM in combination with ionizing radiation (IR) and temozolomide significantly induces apoptosis and DNA fragmentation.

Key Molecule: hsa-miR-128-1 [7]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Human primary brain tumor; Homo sapiens
• Experiment for Molecule Alteration: RT-PCR; Luciferase assay; Western blot; Immunofluorescence
• Experiment for Drug Resistance: Colony formation assay; Cell viability assay; Wound closure assay; Transwell migration assay
• Mechanism Description: In the present study, we demonstrated that the expression of miR-128 and miR-149 was downregulated in glioblastoma, and their overexpression inhibited the invasion of glioblastoma cells by targeting Rap1B-mediated cytoskeletal and related molecular alterations. Moreover, miR-128 and miR-149 enhanced the chemosensitivity of glioblastoma cells to TMZ.

Key Molecule: hsa-miR-203a [70]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Paired glioma and non-cancerous brain tissues model; Homo sapiens
• Experiment for Molecule Alteration: Immunohistochemical; qPCR; Western blot; Luciferase reporter assay
• Experiment for Drug Resistance: MTS assay; Wound healing assay; Transwell cell invasion assay
• Mechanism Description: Recent data has suggested a profound role for microRNAs (miRs) in cancer progression. The present study demonstrated, via quantitative polymerase chain reaction (qPCR) analysis, that miR-203 expression was markedly lower in highly invasive U87MG glioma cells and glioma tissues. Wound healing and Transwell assays demonstrated that restoration of miR-203 expression inhibited U87MG cell migration and invasion. Restoration of miR-203 expression additionally sensitized the cells to temozolomide (TMZ) as determined by MTS assay. By contrast, miR-203 inhibition in A172 cells exerted opposite effects. Bioinformatic analysis combined with experimental analysis revealed that miR-203 directly targeted E2F3 via the conserved miR-203 target site within the E2F3 3'-untranslational region. E2F3 knockdown with specific small hairpin RNA also inhibited U87MG cell migration and invasion, and sensitized them to TMZ. Importantly, miR-203 and E2F3 showed inverse expression patterns in invasive glioma tissues, as demonstrated by qPCR and luciferase assay.

Key Molecule: hsa-miR-34a [4]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MET/MAPK pathway; Regulation; N.A.
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Scratch assay; Flow cytometry; Cell cycle assay
• Mechanism Description: hsa-miR-34a-5p downregulated RAF1 expression, as the signaling factor of the MAPK pathway. The combined treatment significantly downregulated the expression of MET, SRC, and MAP2K1, leading to the inhibition of the MET/MAPK pathway compared to temozolomide. Besides exerting anti-tumoral effects on the cell viability, migration, cell cycle, apoptosis, and clonogenicity of A172 cells, its combination with temozolomide enhanced temozolomide anti-tumoral effect. Compared to temozolomide, the combined treatment significantly decreased CDK4, CDK6, CCND1, and MMP2 expression. hsa-miR-34a-5p targets RAF1, as the signaling factor of the MAPK pathway, and potentiates the temozolomide anti-tumoral effect on A172 cells.

Key Molecule: WT1-AS [6]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Glioblastoma patients; Homo sapiens
• Experiment for Molecule Alteration: Luciferase assays; RT-qPCR; Western blot
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Androgen receptor inhibition sensitizes glioblastoma stem cells to temozolomide by the miR-1/miR-26a-1/miR-487b signature mediated WT1 and FOXA1 silencing

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Lysosome-associated membrane glycoprotein 2 (LAMP2) [13]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.44E-02; Fold-change: -4.21E-02; Z-score: -2.46E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-487b-5p regulates temozolomide resistance of lung cancer cells through lamp2-medicated autophagy.

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: L-glutamine amidohydrolase (GLS) [44]

• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Melanoma [ICD-11: 2C30]
• The Specified Disease: Melanoma
• The Studied Tissue: Skin
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.27E-01; Fold-change: -3.92E-02; Z-score: -6.41E-01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT144 cells; Skin; Homo sapiens (Human); CVCL_0318
• In Vitro Model: SkMEL5 cells; Skin; Homo sapiens (Human); CVCL_0527
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis; Immunohistochemistry assays
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR203 sensitizes MM cells to TMZ by targeting GLS.

References

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