The microRNA signature of patients with sunitinib failure: regulation of UHRF1 pathways by microRNA-101 in renal cell carcinoma

// Yusuke Goto 1, 2 , Akira Kurozumi 1, 2 , Nijiro Nohata 3 , Satoko Kojima 4 , Ryosuke Matsushita 5 , Hirofumi Yoshino 5 , Kazuto Yamazaki 6 , Yasuo Ishida 6 , Tomohiko Ichikawa 2 , Yukio Naya 4 , Naohiko Seki 1 1 Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan 2 Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan 3 Moores Cancer Center, University of California, San Diego, La Jolla, CA, United States of America 4 Department of Urology, Teikyo University Chiba Medical Center, Chiba, Japan 5 Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan 6 Department of Pathology, Teikyo University Chiba Medical Center, Chiba, Japan Correspondence to: Naohiko Seki, email: naoseki@faculty.chiba-u.jp Keywords: microRNA, renal cell carcinoma, sunitinib, miR-101, UHRF1 Received: June 20, 2016 Accepted: July 19, 2016 Published: July 28, 2016 ABSTRACT Molecular targeted therapy is a standard treatment for patients with advanced renal cell carcinoma (RCC). Sunitinib is one of the most common molecular-targeted drugs for metastatic RCC. Molecular mechanisms of sunitinib resistance in RCC cells is still ambiguous. The microRNA (miRNA) expression signature of patients with sunitinib failure in RCC was constructed using a polymerase chain reaction (PCR)-based array. Several miRNAs that were aberrantly expressed in RCC tissues from patients treated with sunitinib were identified in this analysis. MicroRNA-101 (miR- 101) was markedly suppressed in sunitinib treated RCC tissues. Restoration of miR-101 significantly inhibited cell migration and invasion in Caki-1 and 786-O cells. Ubiquitin-like with PHD and ring finger domains 1 ( UHRF1 ) was directly suppressed by miR-101 in RCC cells, and overexpression of UHRF1 was confirmed in sunitinib-treated RCC tissues. The pathways of nucleotide excision repair and mismatch repair were significantly suppressed by knockdown of UHRF1 . Our findings showed that antitumor miR-101 - mediated UHRF1 pathways may be suppressed by sunitinib treatment.