title: Tumor-suppressive microRNA-143/145 cluster targets hexokinase-2 in renal cell carcinoma.
abstract: 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.
authors.affiliation: Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yoshino
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Itesako
authors.forename: Satoko
authors.initials: S
authors.lastname: Kojima
authors.forename: Takashi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tatarano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Naohiko
authors.initials: N
authors.lastname: Seki
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008156:Luciferases; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation
chemical_list: C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D008156:Luciferases; D006593:Hexokinase
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