Downregulation of transient receptor potential cation channel, subfamily C, member 1 (TRPC1) is associated with drug resistance and high histologic grade in ovarian cancer
Purpose: Ovarian cancer (OC) drug resistance, believed to result in treatment failure and death in more than 90% of patients with metastatic OC, is due to a myriad of contributing factors. However, no matter what mechanisms, dysregulation of critical genes essentially play important roles. Transient receptor potential cation channel, subfamily C, member 1 (TRPC1) contributes to various physiological functions, and is involved in the regulation of cancer development. However, the overall studies of TRPC1 with cancer are limited, the study with drug resistance or OC is rare, and the research on TRPC1 with drug resistance in OC has never been reported. In this study, we aimed to explain the associations of TRPC1 with drug resistance in OC.
Methods: The expression of TRPC1 was determined by the microarrays retrieved from Oncomine (https://www.oncomine.org/resource/login.html) and GEO Profiles (http://www.ncbi.nlm.nih.gov/geoprofiles/), and further confirmed by RT-qPCR. The clinical data of 341 OC patients with TRPC1 mRNA expression data in TCGA cohort was retrieved from cBioPortal (http://cbioportal.org). Comprehensive bioinformatics analyses including protein/gene interaction, protein-small molecule/chemical interaction, biological process annotation, microRNA-mRNA interaction and pathway enrichment analysis of microRNAs were performed to clarify the drug resistant-related functions of TRPC1. The data was analyzed by SPSS 20.0 software. P-values of <0.05 were considered to indicate statistically significant differences.
Results: The mRNA expressions of TRPC1 were downregulated by 3.955-fold, 3.681-fold and 3.260-fold in ovarian cancers according to the Welsh Ovarian covering 28 cases of ovarian serous surface papillary carcinoma and 4 cases of ovaries, the Bonome Ovarian covering 185 cases of ovarian carcinomas and 10 cases of ovarian surface epitheliums, and the Yoshihara Ovarian covering 38 cases of ovarian serous adenocarcinomas and 10 cases of peritoneum, respectively, which all were retrieved from the Oncomine. Consistent with the expression in OC tissues, the TRPC1 was downregulated by at least 3-fold in OC cells compared with the expression in normal ovarian surface epithelial cells in accordance with microarray data (GDS3592) retrieved from GEO Profiles. The mRNA expression of TRPC1 were also significantly downregulated in A2780 epithelial OC cells with acquired platinum resistance and carboplatin-resistant OC tissues compared with the expression in their sensitive counterparts according to microarray data (GDS3754 and GDS1381). This result is confirmed by RT-qPCR measurement indicated that the TRPC1 is downregulated in cisplatin-resistant SKOV3 cells and carboplatin resistant A2780 cells, by at least 2-fold changes. Protein/gene interaction indicated that TRPC1 interacted with 21 proteins/genes and 14 of them were associated with drug resistance in OC. Protein-small molecule/chemical interaction indicated that there were 7 chemicals had interactions with TRPC1, and 6 of them were associated with drug resistance or involved in chemotreatment in ovarian and other cancers. Annotation of TRPC1, OC and drug resistance suggested that the TRPC1 might perform drug resistance-related functions in OC through 17 biological processes which involved in the cell cycle, gene expression, and in particular the cell growth and death. mRNA-microRNA interaction indicated that among the top 11 pathways enriched from top 38 microRNAs targeted TRPC1, 8 of them were involved in the regulation of drug resistance in OC, and among the top 10 microRNAs targeted TRPC1, 8 of them were implicated in the drug resistance in ovarian and other cancers. All these results provided a strong possibility that TRPC1 might contribute to drug resistance in OC. Besides, on the basis of the analysis of TRPC1 mRNA with histologic grade of 341 OC patients in TCGA cohort, we revealed that the expression of TRPC1 in OC patients was differed significantly between grade 2 (moderately-differentiated) and grade 3 (poorly-differentiated) (p = 0.006), and low expression of TRPC1 was correlated with high tumor grade.
Conclusion: Downregulation of TRPC1 is potentially associated with drug resistance and high histologic grade in OC. This study would pave the way for further investigation of the drug resistance-related functions of TRPC1.
Cite this article as: Liu X, Zhang J, Li L, Yin F. Downregulation of transient receptor potential cation channel, subfamily C, member 1 (TRPC1) is associated with drug resistance and high histologic grade in ovarian cancer. Int J Cancer Ther Oncol 2015; 3(4):3409.
[This abstract was presented at the BIT’s 8th Annual World Cancer Congress, which was held from May 15-17, 2015 in Beijing, China.]
This work is licensed under a Creative Commons Attribution 3.0 License.
International Journal of Cancer Therapy and Oncology (ISSN 2330-4049)
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