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MiR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC).

ABSTRACT: BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive urological malignancies. MicroRNAs (miRNAs) are post-transcriptional gene regulators in tumor pathophysiology. As miRNAs exert cooperative repressive effects on target genes, studying the miRNA synergism is important to elucidate the regulation mechanism of miRNAs. METHODS:We first created a miRNA-mRNA association network based on sequence complementarity and co-expression patterns of miRNA-targets. The synergism between miRNAs was then defined based on their expressional coherence and the concordance between target genes. The miRNA and mRNA expression were detected in RCC cell lines (786-O) using quantitative RT-PCR. Potential miRNA-target interaction was identified by Dual-Luciferase Reporter assay. Cell proliferation and migration were assessed by CCK-8 and transwell assay. RESULTS:A synergistic miRNA-miRNA interaction network of 28 miRNAs (52 miRNA pairs) with high coexpression level were constructed, among which miR-124 and miR-203 were identified as most tightly connected. ZEB2 expression is inversely correlated with miR-124 and miR-203 and verified as direct miRNA target. Cotransfection of miR-124 and miR-203 into 786-O cell lines effectively attenuated ZEB2 level and normalized renal cancer cell proliferation and migration. The inhibitory effects were abolished by ZEB2 knockdown. Furthermore, pathway analysis suggested that miR-124 and miR-203 participated in activation of epithelial-to-mesenchymal transition (EMT) pathway via regulation of ZEB2. CONCLUSIONS:Our findings provided insights into the role of miRNA-miRNA collaboration as well as a novel therapeutic approach in ccRCC.

SUBMITTER: Chen J

PROVIDER: S-EPMC7014595 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC).

Chen Jiajia J Zhong Yuqing Y Li Liangzhi L

Journal of translational medicine 20200211 1

<h4>Background</h4>Clear cell renal cell carcinoma (ccRCC) is one of the most aggressive urological malignancies. MicroRNAs (miRNAs) are post-transcriptional gene regulators in tumor pathophysiology. As miRNAs exert cooperative repressive effects on target genes, studying the miRNA synergism is important to elucidate the regulation mechanism of miRNAs.<h4>Methods</h4>We first created a miRNA-mRNA association network based on sequence complementarity and co-expression patterns of miRNA-targets. T ...[more]

PMID: 32046742

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Project description:IntroductionAccumulating evidence has demonstrated that circular RNAs (circRNAs) play a key role in the tumorigenesis of various types of cancers, including clear cell renal cell carcinoma (ccRCC).Materials and methodsReverse transcription-quantitative polymerase chain reaction was used to detect the expression of circRNA homeodomain interacting protein kinase 3 (circHIPK3) and microRNAs (miRNAs), including miR-508-3p. The clinical measurement of circHIPK3 was evaluated by Kaplan-Meier survival analysis and receiver operating characteristic analysis. Cell Counting Kit-8 and Transwell chamber assays were performed to determine the changes in the proliferative and metastatic ability of A498 and 786-O cells. C-X-C motif chemokine ligand 13 (CXCL13) protein expression was detected by Western blot analysis. The targeted binding effect between miR-508-3p and circHIPK3 or CXCL13 was confirmed by constructed luciferase and RNA immunoprecipitation (RIP) assays, respectively. Fluorescence in situ hybridization (FISH) assay was used to measure the subcellular localization of circHIPK3 and miR-508-3p.ResultsIt was found that circHIPK3 was markedly upregulated in ccRCC tissue and cell lines, and circHIPK3-upregulation was closely correlated with poor clinicopathological features in patients with ccRCC. It was found that both miR-508-3p and circHIPK3 were localized in the cytoplasm of ccRCC cells. The up- and downregulation of circHIPK3 positively regulated ccRCC cell proliferation and metastasis, and this regulatory effect was reversed by miR-508-3p. Through luciferase and RIP assays, it was confirmed that circHIPK3 could interacted with miR-508-3p. Furthermore, it was revealed that CXCL13, which was negatively correlated with miR-508-3p, was upregulated in ccRCC. It was also shown that CXCL13 was a downstream target of miR-508-3p. miR-508-3p suppressed ccRCC cell proliferation and metastasis by targeting CXCL13. Lastly, it was demonstrated that circHIPK3 promoted CXCL13 to facilitate ccRCC cell proliferation and metastasis by decoying miR-508-3p.ConclusionIn brief, the results of the present study showed that circHIPK3 promoted ccRCC cell proliferation and metastasis by altering miR-5083p/CXCL13 signaling. The present findings might provide a novel target for the molecular treatment of ccRCC.

Dataset Information

MiR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC).

Publications

miR-124 and miR-203 synergistically inactivate EMT pathway via coregulation of ZEB2 in clear cell renal cell carcinoma (ccRCC).

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