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Vitamin D receptor suppresses proliferation and metastasis in renal cell carcinoma cell lines via regulating the expression of the epithelial Ca2+ channel TRPV5.

ABSTRACT: We previously demonstrated that transient receptor potential vanilloid subfamily 5 (TRPV5) expression was decreased in renal cell carcinoma (RCC) compared with that in normal kidney tissues, a finding that was correlated with vitamin D receptor (VDR) expression, but further investigations is warranted. The aim of this study was to elucidate whether VDR could regulate the expression of TRPV5 and affect proliferation and metastasis in RCC. In this study, we used lentivirus to conduct the model of VDR overexpression and knockdown caki-1 and 786-O RCC cell lines in vitro. The results demonstrated that VDR overexpression significantly inhibited RCC cells proliferation, migration and invasion, and promoted apoptosis by the MTT, transwell cell migration/invasion and flow cytometry assays, respectively. However, VDR knockdown in RCC cells had the opposite effect. The RNA-sequence assay, which was assessed in caki-1 cells after VDR overexpression and knockdown, also indicated that significantly differentially expressed genes were associated with cell apoptotic, differentiation, proliferation and migration. RT-PCR and western blot analysis showed that VDR knockdown increased TRPV5 expression and VDR overexpression decreased TRPV5 expression in caki-1 cells. Furthermore, knockdown of TRPV5 expression suppressed the VDR knockdown-induced change in the proliferation, migration and invasion in caki-1 cells. Taken together, these findings confirmed that VDR functions as a tumour suppressor in RCC cells and suppresses the proliferation, migration and invasion of RCC through regulating the expression of TRPV5.

SUBMITTER: Chen Y

PROVIDER: S-EPMC5901920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPancreatic cancer (PC) is one of the most lethal solid malignancies in the world due to its excessive cell proliferation and aggressive metastatic features. Emerging evidences revealed the importance of posttranscriptional modifications of RNAs in PC progression. However, knowledge about the 5-methylcytosine (m5C) RNA modification in PC is still extremely limited. In this study, we attempted to explore the expression changes and clinical significances of 12 known m5C-related genes among PC patients.MethodsA total of 362 normal and 382 tumor specimens from PC patients were examined for candidate m5C-related gene and protein expression by using quantitative PCR (qPCR) and immunohistochemistry (IHC). The proliferation rate of PC cells was detected by MTS assay. Xenograft mouse models were used to assess the role of NSUN6 in PC tumor formation.FindingsThrough analyzing the four Gene Expression Omnibus (GEO) databases, six m5C-related genes shown significant and consistent alterations were selected for further examination in our 3 independent PC cohorts. Finally, we identified the reduction of NSUN6 as a common feature of all PC sample sets examined. NSUN6 expression correlated with clinicopathologic parameters including T stage, and Ki67+ cell rate. Further assessing the transcriptional profiles of 50 PC tissues, we found biological processes associated with cell proliferation like cell cycle and G2M checkpoint were enriched in NSUN6 lower expression group. Helped by in vitro PC cell lines and in vivo xenograft mouse models, we confirmed the role of NSUN6 in regulating cell proliferation and PC tumor growth. Last but also importantly, we also show the good performance of NSUN6 in evaluating tumor recurrence and survival among PC patients.InterpretationOur data suggested that NSUN6 is an important factor involved in regulating cell proliferation of PC, and highlights the potential of novel m5C-based clinical modalities as a therapeutic approach in PC patients.FundingThis study was supported by the National Natural Science Foundation of China (Grant Nos. 81803014, 81802424, and 81802911).

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Vitamin D receptor suppresses proliferation and metastasis in renal cell carcinoma cell lines via regulating the expression of the epithelial Ca2+ channel TRPV5.

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