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 (3 diseases)
  Brain cancer [ICD-11: 2A00]; [2]
  Chronic myeloid leukemia [ICD-11: 2A20]; [2]
  Pituitary cancer [ICD-11: 2F37]; [3]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Brain cancer [ICD-11: 2A00]; [4]
  Lung cancer [ICD-11: 2C25]; [5]
• 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

  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

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• 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: hsa-miR-20b-3p [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR) [1]

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

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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) [7], [8]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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) [9], [10]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR203-TS signaling pathway; Regulation; hsa05206
• 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 [11]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [12]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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) [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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 [13]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [7]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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 [14]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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 [15]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 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 [16]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [17]

• Molecule Alteration: Expressiom; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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) [17]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [18]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell 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 [19]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Tumor suppressor candidate 7 (TUSC7) [19]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [20]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: H19, imprinted maternally expressed transcript (H19) [21]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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: hsa-mir-138 [22]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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; hsa05206
• 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 [23]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 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 [24]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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 [25]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [4]

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

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [19]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 protein 1 (ABCB1) [21]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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-associated protein 1 (MRP1) [21]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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: ATP-binding cassette sub-family G2 (ABCG2) [21]

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

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

Regulation by the Disease Microenvironment (RTDM)

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

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: hsa-miR-151a-3p [26]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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; hsa05206
• 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) [27]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell 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.

Key Molecule: Vimentin (VIM) [27]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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) [27]

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

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Hepatocyte growth factor receptor (MET) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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) [8]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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: Tumor suppressor candidate 3 (TUSC3) [11]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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: Transcription factor Sp1 (SP1) [12]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• 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: Zinc finger E-box-binding homeobox 1 (ZEB1) [10]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Paired box protein Pax-6 (PAX6) [13]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Apoptosis regulator Bcl-2 (BCL2) [14]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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: Serine/threonine-protein kinase mTOR (mTOR) [14]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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: G1/S-specific cyclin-E1 (CCNE1) [15]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 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: DNA repair protein XRCC4 (XRCC4) [16]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: CCN family member 1 (CYR61) [18]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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: Growth protein 4 inhibitor (ING4) [20]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Bcl-2-like protein 11 (BCL2L11) [22]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• 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; hsa05206
• 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: Apoptosis regulator Bcl-2 (BCL2) [23]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: 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: Programmed cell death protein 4 (PDCD4) [24]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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: DNA mismatch repair protein Msh6 (MSH6) [28]

• Molecule Alteration: Mutation; .
• Resistant Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• 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: Endoplasmic reticulum chaperone BiP (HSPA5) [29]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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: Endoplasmin (HSP90B1) [29]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Glioma [ICD-11: 2A00.1]
• 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: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

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

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-126-3p [30]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [31]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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) [32]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Cancer susceptibility 2 (CASC2) [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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: hsa-miR-193a-5p [8]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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 [33]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [12]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• 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: X inactive specific transcript (XIST) [12]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• 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: hsa-mir-181 [34]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• 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 [35]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [36]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 [9]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR203-TS signaling pathway; Regulation; hsa05206
• 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) [7]

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

Key Molecule: Cancer susceptibility 2 (CASC2) [7]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Malignant glioma [ICD-11: 2A00.2]
• 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: qPCR
• 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: hsa-mir-181a [7]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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: 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: hsa-miR-433-3p [37]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell migration assay; Annexin V/fluorescein isothiocyanate (FITC) apoptosis assay
• Mechanism Description: miR433-3p suppresses cell growth and enhances chemosensitivity by targeting CREB in human glioma, the overexpression of CREB can rescue the phenotype changes induced by miR433-3p overexpression.

Key Molecule: hsa-mir-101 [38]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: microRNA-101 reverses temozolomide resistance by inhibition of GSk3beta in glioblastoma.

Key Molecule: hsa-miR-370-3p [39]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• 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: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: TMZ cytotoxicity assay; Colony formation assay; gamma -H2AX foci formation assay
• Mechanism Description: Up-regulation of miR370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression. MGMT was found to be inversely correlated with miR370-3p expression.

Key Molecule: hsa-mir-196b [40]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• 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: Down-regulation of miR-196b increased glioma cell sensitivity to TMZ and E2F1 decreased following transfection with miR-196b inhibitors.

Key Molecule: hsa-miR-7-5p [41]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7-5p suppresses stemness and enhances temozolomide sensitivity of drug-resistant glioblastoma cells by targeting Yin Yang 1.

Key Molecule: hsa-miR-181b-5p [42]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: Upregulation of miR-181b-5p targets Bcl-2 directly and may function as an important modifier to sensitize glioma cells to TMZ.

Key Molecule: hsa-mir-1271 [43]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The chemoresistant cell survival mediated with Bcl-2 was inhibited by overexpression of miR-1271 and was enhanced by depletion of miR-1271.

Key Molecule: hsa-miR-299-5p [44]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; 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: qRT-PCR
• 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: hsa-miR-1268a [45]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• 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
• Mechanism Description: Overexpression of miR-1268a inhibited protein translation of ABCC1, which enhanced sensitivity of GBM cells to TMZ.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [17]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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-101 [17]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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-29c [46]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• 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: hsa-mir-10a [47]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Regulation; hsa04350
• 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: LncRNA RP11-838N2.4 (+) TMZ sensitivity in GBM by serving as a ceRNA, sequestering with miR-10a on an epigenetic level.

Key Molecule: Long non-protein coding RNA (RP11-838N2.4) [47]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Regulation; hsa04350
• 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; Flow cytometry assay
• Mechanism Description: LncRNA RP11-838N2.4 (+) TMZ sensitivity in GBM by serving as a ceRNA, sequestering with miR-10a on an epigenetic level.

Key Molecule: hsa-mir-203 [48]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-203 was reversely associated with migration and invasion, and positively associated with chemosensitivity in glioma cells. E2F3 was shown to be a novel target of miR-203 and E2F3 knockdown exerted a similar effect to that of miR-203 overexpression. These results indicate that miR-203 may act as a tumor suppressor by targeting E2F3 in glioma cells and that miR-203/E2F3 may be a novel candidate for developing rational therapeutic strategies in glioma treatment.

Key Molecule: hsa-mir-128a [49]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: RT-PCR
• 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: hsa-mir-149 [49]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• 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: hsa-mir-125b [50]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: RT-PCR
• 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: hsa-mir-181a [51]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 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: 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: hsa-mir-181 [51]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: qRT-PCR
• 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: hsa-mir-181c [51]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: qRT-PCR
• 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: hsa-mir-181d [51]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: qRT-PCR
• 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: hsa-mir-125b [52]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: PCR
• 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: hsa-mir-17 [53]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: RT-PCR
• 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: hsa-mir-181 [54]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-181b independently predicted chemoresponse to temozolomide and enhanced temozolomide sensitivity via MEk1 downregulation.

Key Molecule: hsa-miR-296-3p [55]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: qRT-PCR
• 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: hsa-mir-21 [56]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: D54MG cells; Brain; Homo sapiens (Human); CVCL_5735
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: TUNEL Analysis
• Mechanism Description: miR-21 is anti-apoptotic, and may promote glioma invasion and proliferation.

Key Molecule: hsa-mir-200c [57]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: Cell metastasis; Inhibition; hsa05205
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: DBTRG-05MG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-200c overexpression in DBTRG cells was able to downregulate both PDHA1 and TIGAR, which are involved in OXPHOS and glycolysis regulation. PDHA1 was described as the major provider of carbon for the TCA in GB. miR-200c overexpression was able to decrease DBTRG cell mobility. The observed effect of miR-200c on the mobility of DBTRG cells could be attributed to miR-200c modulation of E-cadherin levels, and consequent repression of epithelial-mesenchymal transition (EMT).

Key Molecule: hsa-mir-144 [58]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The increase of miR-144 levels, shown to be downregulated in U87 and DBTRG human GB cell lines, as well as in GB tumor samples, promoted the downregulation of mRNA of enzymes involved in bioenergetic pathways, with consequent alterations in cell metabolism, impairment of migratory capacity, and sensitization of DBTRG cells to a chemotherapeutic drug, the dichloroacetate (DCA).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [45]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• 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; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1268a inhibited protein translation of ABCC1, which enhanced sensitivity of GBM cells to TMZ.

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

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

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-26b [59]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• 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: SNB19 TR cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G TR cells; Brain; Homo sapiens (Human); CVCL_0556
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT Assay; Wound healing assay; Transwell invasion assays
• Mechanism Description: miR26b reverses temozolomide resistance via targeting Wee1 in glioma cells. miR26b governed TR-mediate EMT partly due to governing its target Wee1.

Key Molecule: Wee1-like protein kinase (WEE1) [59]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• 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: SNB19 TR cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G TR cells; Brain; Homo sapiens (Human); CVCL_0556
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT Assay; Wound healing assay; Transwell invasion assays
• Mechanism Description: miR26b reverses temozolomide resistance via targeting Wee1 in glioma cells. miR26b governed TR-mediate EMT partly due to governing its target Wee1.

Key Molecule: Dynamin-3 (DNM3) [60]

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

Key Molecule: hsa-mir-221 [60]

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

Key Molecule: hsa-mir-143 [61]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: MAPK/ERK 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
• In Vivo Model: BALB/c nude mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; RT-PCR; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Matrigel assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-143 decreased glioma cell migration, invasion, tube formation and slowed tumor growth and angiogenesis in a manner associated with N-RAS downregulation in vitro and in vivo. miR-143 also sensitizes glioma cells to temozolomide (TMZ),the first-line drug for glioma treatment.

Key Molecule: hsa-mir-143 [61]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: MAPK/ERK 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
• In Vivo Model: BALB/c nude mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; RT-PCR; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Matrigel assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-143 decreased glioma cell migration, invasion, tube formation and slowed tumor growth and angiogenesis in a manner associated with N-RAS downregulation in vitro and in vivo. miR-143 also sensitizes glioma cells to temozolomide (TMZ),the first-line drug for glioma treatment.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor SOX-2 (SOX2) [30]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: High mobility group protein HMGI-C (HMGA2) [31]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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 blotting 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: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [35], [39]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Serine/threonine-protein kinase mTOR (mTOR) [8]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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: TNF receptor-associated factor 6 (TRAF6) [33]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Epidermal growth factor receptor (EGFR) [34]

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

Key Molecule: Aurora kinase A (AURKA) [36]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Thymidylate synthase (TYMS) [9]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Experimental Note: Identified from the Human Clinical 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: Western blot analysis; Immunofluorescence assay
• 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.

Key Molecule: Phosphatase and tensin homolog (PTEN) [7]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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: 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: Phosphatase and tensin homolog (PTEN) [7]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Malignant glioma [ICD-11: 2A00.2]
• 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: Cyclic AMP-responsive element-binding protein 1 (CREB1) [37]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• 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: MTT assay; Transwell migration assay; Annexin V/fluorescein isothiocyanate (FITC) apoptosis assay
• Mechanism Description: miR433-3p suppresses cell growth and enhances chemosensitivity by targeting CREB in human glioma, the overexpression of CREB can rescue the phenotype changes induced by miR433-3p overexpression.

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [38]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 E2F1 (E2F1) [40]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• 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: Transcriptional repressor protein YY1 (TYY1) [41]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• 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-7-5p suppresses stemness and enhances temozolomide sensitivity of drug-resistant glioblastoma cells by targeting Yin Yang 1.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [42]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: Upregulation of miR-181b-5p targets Bcl-2 directly and may function as an important modifier to sensitize glioma cells to TMZ.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [43]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The chemoresistant cell survival mediated with Bcl-2 was inhibited by overexpression of miR-1271 and was enhanced by depletion of miR-1271.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [44]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [17]

• Molecule Alteration: Methylation; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Western blot analysis
• 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: Transcription factor Sp1 (SP1) [46]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• 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: Transcription factor E2F3 (E2F3) [48]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-203 was reversely associated with migration and invasion, and positively associated with chemosensitivity in glioma cells. E2F3 was shown to be a novel target of miR-203 and E2F3 knockdown exerted a similar effect to that of miR-203 overexpression. These results indicate that miR-203 may act as a tumor suppressor by targeting E2F3 in glioma cells and that miR-203/E2F3 may be a novel candidate for developing rational therapeutic strategies in glioma treatment.

Key Molecule: Ras-related protein Rap-1b (RAP1B) [49]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: NF-kappa-B inhibitor-interacting Ras-like protein 2 (NKIRAS2) [50]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) [50]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: Ras-related protein Rap-1b (RAP1B) [51]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 blotting 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: E3 SUMO-protein ligase PIAS3 (PIAS3) [52]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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 blotting 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: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [53]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• 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: MAPK/ERK kinase 1 (MEK1) [54]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• 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 blotting 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: Potassium voltage-gated channel subfamily H member 1 (KCNH1) [55]

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

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chronic myelogenous leukemia [ICD-11: 2A20.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562-VP16 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: MTT assay
• 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 Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Chronic myelogenous leukemia [ICD-11: 2A20.3]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: K562-VP16 cells; Blood; Homo sapiens (Human); CVCL_0004
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: MTT assay
• 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.

Primary central nervous system lymphoma [ICD-11: 2A8Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-370 [62]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Primary central nervous system lymphoma [ICD-11: 2A8Z.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Raji Burkitt cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our study described a new miR-370-mediated mechanism of MGMT regulation in PCNSL. We first showed that miR-370 was downregulated in PCNSL tissues, while MGMT was inversely overexpressed. It was also observed that miR-370 suppressed the expression of MGMT. Additionally, upregulation of miR-370 significantly increased TMZ sensitivity dependent of MGMT, thus suppressed Raji cell proliferation and induced apoptosis in vitro. These results suggest that miR-370 is a potential target in PCNSL treatment.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [62]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Primary central nervous system lymphoma [ICD-11: 2A8Z.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Raji cells; Brain; Homo sapiens (Human); CVCL_0511
• In Vitro Model: Primary central nervous system lymphoma; Spinal cord; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-370 was downregulated in PCNSL tissues, while MGMT was inversely overexpressed.TMZ sensitivity consistently correlated with the overexpression of miR-370 and inhibition of MGMT; miR-370 affected PCNSL cell proliferation and increased apoptosis via MGMT.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [62]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Primary central nervous system lymphoma [ICD-11: 2A8Z.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Raji Burkitt cells; Bone; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our study described a new miR-370-mediated mechanism of MGMT regulation in PCNSL. We first showed that miR-370 was downregulated in PCNSL tissues, while MGMT was inversely overexpressed. It was also observed that miR-370 suppressed the expression of MGMT. Additionally, upregulation of miR-370 significantly increased TMZ sensitivity dependent of MGMT, thus suppressed Raji cell proliferation and induced apoptosis in vitro. These results suggest that miR-370 is a potential target in PCNSL treatment.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-487b-5p [5]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: 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: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-487b-5p regulates temozolomide resistance of lung cancer cells through lamp2-medicated autophagy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Lysosome-associated membrane glycoprotein 2 (LAMP2) [5]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: 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

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-203 [63]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• 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: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR203 sensitizes MM cells to TMZ by targeting GLS.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: L-glutamine amidohydrolase (GLS) [63]

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

Pituitary cancer [ICD-11: 2F37]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA mismatch repair protein Msh6 (MSH6) [3]

• Molecule Alteration: Structural variation; Copy number loss
• Resistant Disease: Pituitary cancer [ICD-11: 2F37.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Low throughput experiment assay
• Mechanism Description: Loss of MSH6 occurred during the progression from an atypical prolactinoma to a pituitary carcinoma, which may have caused resistance to TMZ treatment.

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