Tumor suppressor genes associated with drug resistance in ovarian cancer (Review)

Abstract

Ovarian cancer is a fatal gynecological cancer and a major cause of cancer-related mortality worldwide. The main limitation to a successful treatment for ovarian cancer is the development of drug resistance to combined chemotherapy. Tumor suppressor genes (TSGs) are wild-type alleles of genes which play regulatory roles in diverse cellular activities, and whose loss of function contributes to the development of cancer. It has been demonstrated that TSGs contribute to drug resistance in several types of solid tumors. However, an overview of the contribution of TSGs to drug resistance in ovarian cancer has not previously been reported. In this study, 15 TSGs responding to drug resistance in ovarian cancer were reviewed to determine the relationship of TSGs with ovarian cancer drug resistance. Furthermore, gene/protein-interaction and bio-association analysis were performed to demonstrate the associations of these TSGs and to mine the potential drug resistance-related genes in ovarian cancer. We observed that the 15 TSGs had close interactions with each other, suggesting that they may contribute to drug resistance in ovarian cancer as a group. Five pathways/processes consisting of DNA damage, apoptosis, cell cycle, DNA binding and methylation may be the key ways with which TSGs participate in the regulation of drug resistance. In addition, ubiquitin C (UBC) and six additional TSGs including the adenomatous polyposis coli gene (APC), death associated protein kinase gene (DAPK), pleiomorphic adenoma gene-like 1 (PLAGL1), retinoblastoma susceptibility gene (RB1), a gene encoding an apoptosis-associated speck-like protein (PYCARD/ASC) and tumor protein 63 (TP63), which had close interactions with the 15 TSGs, are potential drug resistance-related genes in ovarian cancer.

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

“…Many of the genes with increased expression, including granzyme B (GZMB), 29 a calcium binding protein (S100A6), 30 a gap junction protein (GJA1), 31 and a cyclin-dependent kinase inhibitor (CDKN2A), 32 have been reported to have a role in cell death and/or apoptosis. Several genes showing decreased expression, including the inhibitory receptor of peripheral mononuclear cells (LAIR1), 33 a conserved cysteine-rich protein (PLAC8), 34 an apoptosis-associated speck-like protein (PYCARD), 35 and a receptor tyrosine kinase (ERBB3), 36 have also been reported to have a role in cell death. CARD11, a caspase recruitment domain-containing protein, has decreased expression and been reported to interact with the proapoptotic BCL10 protein.…”

Upregulation of NEK2 is associated with drug resistance in ovarian cancer

“…For example, on the basis of comprehensive bioinformatic analysis, Yin et al (77) reported that SPARCL1 and CCL21 are associated with drug resistance in ovarian cancer. Similarly, 15 TSGs associated with drug resistance in ovarian cancer were analyzed by comprehensive bioinformatics to overview the relationship of the 15 TSGs with drug resistance and to discover potential TSGs related with drug resistance (49).…”

“…The expression of DAPK1 and DAPK2 is altered in multi-drug-resistant gastric cancer cell lines and thus these genes may be an integral part of the mechanisms responsible for chemoresistance (48). In ovarian cancer, DAPK1 has direct interactions with FBXO32, PDCD4, PTEN, TP53 and TP73, and has indirect interactions with BRCA1, BRCA2, CDKN1A, IL24, MLH1 and SULF1, which are all involved in drug resistance in ovarian cancer, suggesting its potential role in drug resistance in ovarian cancer (49). As for CDK2, a previous study revealed that cisplatin consistently induces transient S-phase arrest by inhibiting the CDK2/cyclin A complex in the S-phase at 12 h after treatment with cisplatin or DAP in combination with the mitotic inhibitor nocodazole and also potently inhibits G1-phase CDK2/cyclin E activities at 18 h (50), indicating that CDK2 can directly respond to cisplatin in ovarian cancer cells.…”

“…Given that the overexpression of miR-486-5p is closely correlated with the downregulated expression of ARHGAP5 in lung tumor tissues, which considerably inhibits lung cancer cell migration and invasion, miR-486-5p may act as a tumor suppressor contributing to the progression and metastasis of non-small cell lung cancer (76). Actually, the biological processes including cell proliferation, invasion, growth and metastasis in which miR-216b and miR-486-5p are involved are closely related to the development of drug resistance in cancers (49,77), and the annotation of biological processes also suggests that cell proliferation and growth are associated with drug resistance. All these results indicate that miR-216b and miR-486-5p may be associated with drug resistance in an indirectly way.…”

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

“…In addition, apoptosis, which is associated with the expression of specific 'death' genes and downregulation of 'survival' counterparts, is crucial in determining the response to chemotherapeutic agents (8,9). However, regardless of the mechanisms, abnormal expression of drug resistance-related genes often plays important roles in drug resistance (10).…”