Disease Information

General Information of the Disease (ID: DIS00107)

• Name: HPV-related cervical cancer
• ICD: ICD-11: 2E67

Type(s) of Resistant Mechanism of This Disease

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [1]

• Resistant Disease: HPV-related cervical cancer [ICD-11: 2E67.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: GSK3 pathway; Activation; hsa04340
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vitro Model: C33A cells; Uterus; Homo sapiens (Human); CVCL_1094
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We examined the significance of HPV and HPV-driven pathways in CSCC pathogenesis and specially focused on its contribution to the neoplasm's severity, including its induction of rapid proliferation, survival, invasiveness, and chemoresistance. We hypothesized that the expression of the viral oncoproteins E6/E7, in addition to activation of the glycogen synthase kinase-3 (GSK3)alpha/beta signaling pathways, could influence the biology of CSCC. We used liquid N2 frozen/fresh human CSCC tissues and adjacent normal (AN) and chemoradiation-resistant CSCC to determine HPV16/18 E6 and HPV16 E7 and the expression and activation of the pERK1/2 and GSK3 pathways. Cisplatin-resistant cervical cancer cell lines, both HPV positive (HeLa and SiHa) and HPV negative (C33A), were created and used as a model to investigate cervical cancer invasion and resistance. We provide evidence that there is an increased dependence of GSK3beta signaling in HPV16/18-induced CSCC that promotes chemoresistance and invasiveness.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [2], [3]

• Sensitive Disease: HPV-related endocervical adenocarcinoma [ICD-11: 2E67.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization. And overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [4], [5]

• Sensitive Disease: HPV-related endocervical adenocarcinoma [ICD-11: 2E67.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively. And the antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

Vincristine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [4], [5]

• Sensitive Disease: HPV-related endocervical adenocarcinoma [ICD-11: 2E67.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: SGC7901/VCR cells; Gastric; Homo sapiens (Human); CVCL_VU58
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively. And the antiapoptotic protein BCL2 is upregulated, whereas miR-181b is downregulated in both SGC7901/VCR and A549/CDDP cells, compared with SGC7901 and A549 cells, respectively. Enforced miR-181b expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively.

References

• Ref 1: Glycogen synthase kinase-3Beta inactivation promotes cervical cancer progression, invasion, and drug resistance .Biotechnol Appl Biochem. 2021 Sep 23. doi: 10.1002/bab.2258. Online ahead of print. 10.1002/bab.2258
• Ref 2: MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition. Cancer Res. 2012 Aug 15;72(16):4037-46. doi: 10.1158/0008-5472.CAN-12-0103. Epub 2012 Jul 3.
• Ref 3: Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity. Mol Cancer Res. 2013 Dec;11(12):1564-73. doi: 10.1158/1541-7786.MCR-13-0292. Epub 2013 Oct 2.
• Ref 4: miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines. Int J Cancer. 2010 Dec 1;127(11):2520-9. doi: 10.1002/ijc.25260.
• Ref 5: miR-497 modulates multidrug resistance of human cancer cell lines by targeting BCL2. Med Oncol. 2012 Mar;29(1):384-91. doi: 10.1007/s12032-010-9797-4. Epub 2011 Jan 22.