These authors contributed equally to this work.
Tumor-suppressive microRNA-143/145 cluster targets hexokinase-2 in renal cell carcinoma
Article first published online: 11 OCT 2013
© 2013 Japanese Cancer Association
Volume 104, Issue 12, pages 1567–1574, December 2013
How to Cite
(Cancer Sci 2013; 104: 1567–1574)
- Issue published online: 6 DEC 2013
- Article first published online: 11 OCT 2013
- Accepted manuscript online: 6 SEP 2013 09:20AM EST
- Manuscript Accepted: 31 AUG 2013
- Manuscript Revised: 19 AUG 2013
- Manuscript Received: 5 JUN 2013
- Ministry of Education, Sciences, Sports, and Culture of Japan
- Science Research (B and C). Grant Numbers: 23501298, 23592340
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 miRNA 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 miRNAs 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 (HK2) 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 HK2. In RCC clinical specimens, the expression of HK2 was significantly higher in cancer tissues than in non-cancerous tissues. Silencing HK2 suppressed RCC cell proliferation and invasion, suggesting that HK2 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 HK2.