The network of DAB2IP-miR-138 in regulating drug resistance of renal cell carcinoma associated with stem-like phenotypes

// Eun-Jin Yun 1, * , Jiancheng Zhou 1, 2 , Chun-Jung Lin 1 , Shan Xu 1, 3 , John Santoyo 1 , Elizabeth Hernandez 1 , Chih-Ho Lai 4 , Ho Lin 5 , Dalin He 3 and Jer-Tsong Hsieh 1, 6, * 1 Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 2 Department of Urology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China 3 Department of Urology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710049, China 4 Department of Microbiology and Immunology, Chang Gung University, Taoyuan 333, Taiwan 5 Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan 6 Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung 40447, Taiwan, Republic of China * These authors contributed equally to this work Correspondence to: Eun-Jin Yun, email: eun-jin.yun@utsouthwestern.edu Jer-Tsong Hsieh, email: jt.hsieh@utsouthwestern.edu Keywords: miR-138, DAB2IP, cancer stem cell, drug resistance Received: March 21, 2017      Accepted: April 27, 2017      Published: May 09, 2017 ABSTRACT Targeted therapy is a standard of care for metastatic renal cell carcinoma (RCC) but the response rate is not overwhelmed, which only prolongs a short survival of patients due to the onset of therapeutic resistance. Although the mechanisms are not fully understood, the presence of cancer initiating cells (CIC) may underlie the drug resistance. Nevertheless, identifying CIC phenotypes with its biomarkers in RCC appear to be diverse and controversial from many reports. In this study, we took a different approach to focus on the regulatory mechanism in RCC-CIC and unveil DAB2IP-mediated miR-138 expression that plays a critical role in modulating stem-like phenotypes in RCC via targeting the ABC transporter (ABCA13) as well as oncogenic histone methyltransferase EZH2 while down regulation of miR-138 gene expression in RCC is due to epigenetic gene silencing by DNA methyltransferase 1 (DNMT1). We also characterize the individual mechanism by which ABCA13 in RCC-CIC contributes to its drug resistance and. EZH2 maintain stem-like phenotypes. Noticeably, elevated expression of ABCA13 and EZH2 is correlated with overall survival of RCC patients, which can be used as potential prognostic markers. Taken together, this study demonstrates a potent and unique pathway of DAB2IP-mediated miR-138 in modulating CIC phenotypes during RCC progression and also offers a new therapeutic strategy of targeting drug resistant RCC.