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464 TUMOR-SUPPRESSIVE MIR-135A INHIBITS CANCER CELL PROLIFERATION BY TARGETING THE C-MYC ONCOGENE IN RENAL CELL CARCINOMA

2013; Lippincott Williams & Wilkins; Volume: 189; Issue: 4S Linguagem: Inglês

10.1016/j.juro.2013.02.1855

1527-3792

Hideo Hidaka, H. Yoshino, Hideki Enokida, Takeshi Yamasaki, Toshihiko Itesako, Tomokazu Yonezawa, Naohiko Seki, Masayuki Nakagawa,

Renal and related cancers

You have accessJournal of UrologyKidney Cancer: Basic Research (III)1 Apr 2013464 TUMOR-SUPPRESSIVE MIR-135A INHIBITS CANCER CELL PROLIFERATION BY TARGETING THE C-MYC ONCOGENE IN RENAL CELL CARCINOMA Hideo Hidaka, Hirohumi Yoshino, Hideki Enokida, Takeshi Yamasaki, Toshihiko Itesako, Tomokazu Yonezawa, Naohiko Seki, and Masayuki Nakagawa Hideo HidakaHideo Hidaka Kagoshima, Japan More articles by this author , Hirohumi YoshinoHirohumi Yoshino Kagoshima, Japan More articles by this author , Hideki EnokidaHideki Enokida Kagoshima, Japan More articles by this author , Takeshi YamasakiTakeshi Yamasaki Kagoshima, Japan More articles by this author , Toshihiko ItesakoToshihiko Itesako Kagoshima, Japan More articles by this author , Tomokazu YonezawaTomokazu Yonezawa Kagoshima, Japan More articles by this author , Naohiko SekiNaohiko Seki Chiba, Japan More articles by this author , and Masayuki NakagawaMasayuki Nakagawa Kagoshima, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1855AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Our recent microRNAs (miRNAs) expression signatures of renal cell carcinoma (RCC) revealed that downregulation of miR-135a was frequent event in cancer tissues, suggesting that it may function as a tumor suppressive miRNA. The aim of this study is to investigate the functional significance of miR-135a and to identify miR-135a-mediated molecular pathways in RCC. METHODS We evaluated miR-135a expression in RCC cell lines (caki2 and A498) and 38 RCC clinical specimens by real-time PCR. To investigate the functional role of miR-135a, we performed gain-of-function studies by using miR-135a transfectants (TFs). Gene expression analysis of the transfectants by oligo-microarray analysis was carried out to identify molecular targets and signaling pathways regulated by miR-135a. The GENECODIS software assigned a number of the putative miRNA-targeted genes to the known pathways in KEGG. In this study, we focused on the c-MYC gene, which belongs to Cell cycle pathway and has a putative miR-135a binding site in its 3`fUTR region. A luciferase reporter assay was carried out to determine whether 3`fUTR of c-MYC has an actual biding site for miR-135a. To confirm whether miR-135a regulates molecular pathways in RCC, we investigated the expression levels of genes in Cell cycle pathway in 53 RCC specimens and 23 adjacent normal kidney specimens using available data sets (GSE36895 and GSE22541). RESULTS MiR-135a expression in the RCC cell lines was significantly lower than that in normal kidney tissues. XTT and invasion assays demonstrated that cell viability was significantly inhibited in the miR-135a TFs compared with the control TFs. Cell cycle assay showed that G0/G1 arrest was induced in the miR-135a TFs. Gene expression analysis showed that 570 genes were down-regulated in the miR-135a TFs. These genes were classified into 25 signaling pathways in KEGG pathway categories. Luciferase reporter assay showed that c-MYC was directly regulated by miR-135a. In clinical specimens, expression levels of c-MYC and CCND1, which is in a c-MYC downstream, were significantly up-regulated in RCC specimens compared with the normal specimens. CONCLUSIONS miR-135a was significantly down-regulated in RCC clinical specimens and appeared to function as a tumor suppressor in RCC through inhibition of c-MYC and cell cycle progression. Identification of such tumor-suppressive, miRNA-mediated cancer pathways in human RCC could provide new information on potential therapeutic targets in the treatment of RCC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e190 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hideo Hidaka Kagoshima, Japan More articles by this author Hirohumi Yoshino Kagoshima, Japan More articles by this author Hideki Enokida Kagoshima, Japan More articles by this author Takeshi Yamasaki Kagoshima, Japan More articles by this author Toshihiko Itesako Kagoshima, Japan More articles by this author Tomokazu Yonezawa Kagoshima, Japan More articles by this author Naohiko Seki Chiba, Japan More articles by this author Masayuki Nakagawa Kagoshima, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...