Impact of novel oncogenic pathways regulated by anti-tumor miR-451a in renal cell carcinoma

Summary

Recent analyses of our microRNA (miRNA) expression signatures obtained from several types of cancer have provided novel information on their molecular pathology. In renal cell carcinoma (RCC), expression of microRNA-451a (miR-451a) was significantly downregulated in patient specimens and low expression of miR-451a was significantly associated with poor prognosis of RCC patients (p = 0.00305) based on data in The Cancer Genome Atlas (TCGA). The aims of the present study were to investigate the anti-tumor roles of miR-451a and to identify novel oncogenic networks it regulated in RCC cells. Ectopic expression of miR-451a significantly inhibited cancer cell migration and invasion by RCC cell lines, suggesting that miR-451a had anti-tumor roles. To identity oncogenes regulated by miR-451a in RCC cells, we analyzed genome-wide gene expression data and examined information in in silico databases. A total of 16 oncogenes and were found to be possible targets of miR-451a regulation. Interestingly, high expression of 9 genes (PMM2, CRELD2, CLEC2D, SPC25, BST2, EVL, TBX15, DPYSL3 and NAMPT) was significantly associated with poor prognosis. In this study, we focused on Phosphomannomutase 2 (PMM2), which was the most strongly associated with prognosis. Overexpression of PMM2 was detected in clinical specimens and Spearman's rank test indicated a negative correlation between the expression levels of miR-451a and PMM2 (p = 0.0409). Knockdown of PMM2 in RCC cells inhibited cancer cell migration and invasion, indicating overexpression of PMM2 could promote malignancy. Analytic strategies based on anti-tumor miRNAs is an effective tool for identification of novel pathways of cancer.

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