Downregulation of transient receptor potential cation channel, subfamily C, member 1 contributes to drug resistance and high histological grade in ovarian cancer

Abstract

Abstract. Transient receptor potential cation channel, subfamily C, member 1 (TRPC1) participates in many physiological functions but has also been implicated in cancer development. However, little is known about the role of TRPC1 in ovarian cancer (OC), including the drug resistance of these tumors. In the present study, a significant and consistent downregulation of TRPC1 in drug-resistant OC tissues/cells was determined using real-time quantitative polymerase chain reaction assays and the microarrays deposited in Oncomine and Gene Expression Omnibus (GEO) Profiles. Protein/geneprotein/gene and protein-chemical interactions indicated that TRPC1 interacts with 14 proteins/genes and 6 chemicals, all of which are involved in the regulation of drug resistance in OC. Biological process annotation of TRPC1, OC, and drug resistance indicated a role for TRPC1 in drug-resistance-related functions in OC, mainly via the cell cycle, gene expression and cell growth and cell death. Analysis of mRNA-microRNA interactions showed that 8 out of 11 major pathways enriched from 38 predominant microRNAs targeting TRPC1 were involved in the regulation of drug resistance in OC, and 8 out of these top 10 microRNAs were implicated in the drug resistance in ovarian and other cancers. In a clinical analysis using data obtained from The Cancer Genome Atlas project (TCGA) cohort on 341 OC patients, TRPC1 expression was found to differ significantly between grade 2 and grade 3 tumors, with low-level expression correlating with higher tumor grade. This is the first report to show a potential association between the downregulation of TRPC1 and both drug resistance and high histological tumor grade in OC. Our results provide the basis for further investigations of the drug-resistance-related functions of TRPC1 in OC and other forms of cancer.

Low expression of KCNN3 may affect drug resistance in ovarian cancer

“…Possible networks of protein or gene interactions with KCNN3 included 49 gene or gene products associated with drug-resistance in OC, which further explained its association with drug resistance. These genes/gene products included 25 oncogenes ( 35 ); URI1, STAT3, SRC, RSF1, PIK3CA, NOTCH3, NINL, NFKB1, MYC, MIEN1, MET, KRAS, JUN, IKBKE, FOS, ERBB2, EGFR, DAXX, CUZD1, CLU, BCL2, BAX, AKT2, AKT1 and ACTN4 and 15 tumor suppressors ( 36 ) including BRCA1, BRCA2, CHEK2, FBXO32, MLH1, SULF1, IL24, CDKN2A, CDKN1A, TP53, TP73, PDCD4, PTEN, RASSF1 and WWOX, as well as 9 other genes, including CCL21 and SPARCL1 ( 37 ), GGNBP2 and RNASET2 ( 38 ), NEK2 ( 39 ), NEK11 ( 40 ), ALDH1A2 and ADH1B ( 41 ) and TRPC1 ( 42 ). KCNN3 directly interacted with 18 of these genes or gene products, and exhibited indirect interactions with the rest ( Fig.…”

“…Specifically, acquisition of drug resistance in multiple myeloma is associated with the suppression of inositol 1,4,5-triphosphate receptor type 1, phospholipase C, transient receptor potential cation channel subfamily M member 7 and TRPC1 expression, and reducing the expression of TRPC1 markedly inhibits drug-induced cell death ( 51 ). It was observed that decreased expression of TRPC1 is associated with drug resistance in OC ( 42 ), and the protein interacts with KCNN3. Thus, it was concluded that low expression of KCNN3 may contribute to drug resistance via interactions with TRPC1, through inhibition of drug induced cell death.…”

Cross-validation of genes potentially associated with overall survival and drug resistance in ovarian cancer

“…In this analysis, in the case of two probe sets that target one gene, only the probe set with significant variability was retained. In the case of more than three probe sets that target one gene, the set exhibiting the most divergent expression was excluded and the set with significant variability was retained (12).…”

Exploring the Therapeutic Potential of Membrane Transport Proteins: Focus on Cancer and Chemoresistance

“…Moreover, the altered expression profile of various members of the TRPC subfamily has been associated with chemoresistance. For instance, TRPC1 expression is significantly decreased in cisplatin-resistant (A2780 and SKOV3) and carboplatin-resistant (A2780) ovarian cancer cell lines, suggesting that the reduced expression of TRPC1 is linked to chemoresistance [169]. On the contrary, TRPC5 has increased in 5-FU-resistant colorectal cancer cells HCT-8/5-FU and LoVo/5-FU cell lines, therefore blockade of TRPC5 promotes chemosensitivity in these cells [170].…”