Tumor‐suppressive micro RNA ‐143/145 cluster targets hexokinase‐2 in renal cell carcinoma

Our recent studies of microRNA (miRNA) expression signatures have indicated that the miR‐143/145 cluster is significantly downregulated in several types of cancer and represents a putative tumor‐suppressive mi RNA in human cancers. The aim of this study was to investigate the functional significance of the miR‐143/145 cluster in cancer cells and to identify novel molecular targets of the miR‐143/145 cluster in renal cell carcinoma ( RCC ). The expression levels of miR‐143 and miR‐145 were significantly downregulated in RCC tissues compared with adjacent non‐cancerous tissues. A significant positive correlation was recognized between miR‐143 and miR‐145 expression. Restoration of mature miR‐143 or miR‐145 in 786‐O and A498 RCC cells revealed that both mature mi RNA s significantly inhibited cancer cell proliferation and invasion, suggesting that the miR‐143/145 cluster functioned as a tumor suppressor in RCC . Gene expression data and in silico database analysis showed that the hexokinase‐2 ( HK 2 ) gene, which encodes a glycolytic enzyme crucial for the Warburg effect in cancer cells, was a candidate target of the miR‐143/145 cluster. Luciferase reporter assays showed that both miR‐143 and miR‐145 directly regulated HK 2 . In RCC clinical specimens, the expression of HK 2 was significantly higher in cancer tissues than in non‐cancerous tissues. Silencing HK 2 suppressed RCC cell proliferation and invasion, suggesting that HK 2 has oncogenic functions in RCC . Thus, our data showed that loss of the tumor‐suppressive miR‐143/145 cluster enhanced RCC cell proliferation and invasion through targeting HK 2 .