Establishment of a miRNA-mRNA regulatory network in metastatic renal cell carcinoma and screening of potential therapeutic targets
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This study aimed to screen effective diagnosis or treatment biomarkers for renal cell carcinoma, especially for metastatic renal cell carcinoma (mRCC) based on microRNA (miRNA) and messenger RNA (mRNA) genechip, and their regulatory network. The differential expressions of miRNAs and mRNAs were examined by miRNA and mRNA gene-chip analyses, respectively, in patients with either localized renal cell carcinoma (lRCC) or mRCC, and a miRNA-mRNA regulatory network was established. Subsequently, the regulation of selected mRNAs by miRNAs was validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and dual-luciferase reporter gene assay. Thirty-one up-regulated miRNAs, 196 down-regulated miRNAs, 214 up-regulated mRNAs, and 156 down-regulated mRNAs were identified in patients with mRCC. In total, 1315 miRNA-mRNA pairs, involving 34 miRNAs and 225 mRNAs, were established. The expression profiles of four up-regulated miRNAs, hsa-miR-139-5p, hsa-miR-140-3p, hsa-miR-151a-3p, and hsa-miR-204-5p, and four down-regulated miRNAs, hsa-miR-409-3p, hsa-miR-671-3p, hsa-miR-1203, and hsa-miR-1290, were consistent with the results from the miRNA gene-chip analysis. The expression profiles of NEU2, MASP1, MCL1, ARHGAP11A, HOXA1, and CLDN8 were consistent with the results from the mRNA gene-chip analysis. In vitro, hsa-miR-140-3p bound to the 3′ untranslated region (3′-UTR) of the MASP1 mRNA and down-regulated its expression. Similarly, hsa-miR-151a-3p, hsa-miR-671-3p, and hsa-miR-1290 bound to the 3′-UTRs of the MCL1, HOXA1, and HOXA1 mRNAs, respectively, and down-regulated their expressions. However, binding by hsa-miR-140-3p, hsa-miR-671-3p, or hsa-miR-1290 did not down-regulate the expressions of NEU2, ARHGAP11A, and CLDN8, respectively. This study provides a significant reference of investigating the pathogenesis of mRCC and the subsequent screening of potential therapeutic targets.
KeywordsLocalized renal cell carcinoma Metastatic renal cell carcinoma Genechip Regulatory network Molecular target Screening
This work was financially supported by the National Natural Science Foundation of China (no. 81100483) and the National High Technology Research and Development Program of China (863 program; no. 2012AA021100).
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