MP39-09 IMPACT OF MICRORNA EXPRESSION SIGNATURE OF PATIENTS WITH TKI FAILURE: REGULATION OF MIR-10A-5P PATHWAYS IN RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I1 Apr 2017MP39-09 IMPACT OF MICRORNA EXPRESSION SIGNATURE OF PATIENTS WITH TKI FAILURE: REGULATION OF MIR-10A-5P PATHWAYS IN RENAL CELL CARCINOMA Takayuki Arai, Atsushi Okato, Akira Kurozumi, Mayuko Kato, Yusuke Goto, Satoko Kojima, Yukio Naya, Tomohiko Ichikawa, and Naohiko Seki Takayuki AraiTakayuki Arai More articles by this author , Atsushi OkatoAtsushi Okato More articles by this author , Akira KurozumiAkira Kurozumi More articles by this author , Mayuko KatoMayuko Kato More articles by this author , Yusuke GotoYusuke Goto More articles by this author , Satoko KojimaSatoko Kojima More articles by this author , Yukio NayaYukio Naya More articles by this author , Tomohiko IchikawaTomohiko Ichikawa More articles by this author , and Naohiko SekiNaohiko Seki More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1183AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Currently developed tyrosine kinase inhibitors (TKIs) based molecular targeted therapies have improved the prognosis of patients with advanced renal cell carcinoma (RCC). However, RCC cells acquire the resistance to TKI drugs during the course of sequencing treatment of TKIs. The overall survival of the patients with TKI-treatment failure is extremely poor and no effective treatment resumes for this disease. To identify key molecules and novel pathways involved in the resistance of TKI therapies for RCC is needed. In this study, we constructed a miRNA expression signature to identify pathways activated by TKI-treatment using autopsy specimens from patients with TKI-treatment failure. We have sequentially identified tumor-suppressive miRNAs and these miRNAs regulated RCC pathways based on the signature. The aim of this study was to investigate the functional significance of miR-10a-5p and to identify the molecular targets and pathways mediated by miR-10a-5p in RCC cells. METHODS TCGA database was applied to investigate the clinical outcome of the patients. Gain-of-function studies were performed using transfection of mature miR-10a-5p into RCC cell lines. Genome-wide gene expression analysis and in silico analysis were applied to investigate molecular targets regulated by miR-10a-5p in RCC cells. RESULTS The expression levels of miR-10a-5p were significantly reduced in RCC clinical specimens and RCC cell lines compared with non-cancerous kidney tissues (P < 0.001). TCGA data showed that the overall survival of low miR-10a-5p expression group was significantly shorter than that of high expression group (P = 0.00408). Restoration of miR-10a-5p significantly inhibited cancer cell migration and invasion in RCC cell lines (P < 0.0001). Spindle and kinetochore associated complex subunit 1 (SKA1) was identified as a direct target gene of miR-10a-5p by genome-wide gene expression analysis and in silico analysis. Overexpression of SKA1 was observed in RCC clinical specimens. Moreover, the overall survival of high SKA1 expression group was significantly shorter than that of low expression group by TCGA analysis (P = 1.44E-07). CONCLUSIONS Tumor-suppressive miR-10a-5p was identified based on the miRNA signature. Overexpression of SKA1 might be involved in RCC aggressiveness metastasis and drug resistance. Elucidation of tumor-suppressive miRNAs regulated molecular pathways and targets could provide new information on potential therapeutic strategies in the disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e496 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takayuki Arai More articles by this author Atsushi Okato More articles by this author Akira Kurozumi More articles by this author Mayuko Kato More articles by this author Yusuke Goto More articles by this author Satoko Kojima More articles by this author Yukio Naya More articles by this author Tomohiko Ichikawa More articles by this author Naohiko Seki More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...