miR-503-5p confers drug resistance by targeting PUMA in colorectal carcinoma

// Ke Xu 1, 2, * , Guo Chen 3, * , Yanyan Qiu 1, 2, 4 , Zeting Yuan 1 , Hongchang Li 4 , Xia Yuan 5 , Jian Sun 1, 2 , Jianhua Xu 2 , Xin Liang 6 , Peihao Yin 2, 4 1 Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China 2 Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Medicine, Shanghai 200062, PR China 3 Department of Radiation Oncology, School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, USA 4 Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China State 5 Department of Pharmacy, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China 6 State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China * These authors have contributed equally to this work Correspondence to: Peihao Yin, email: yinpeihao1975@hotmail.com Ke Xu, email: cola519@163.com Xin Liang, email: xin.liang@ecust.edu.cn Keywords: colorectal carcinoma, multidrug-resistance, miR-503-5p, PUMA, p53 Received: August 24, 2016      Accepted: January 22, 2017      Published: February 21, 2017 ABSTRACT The development of multidrug-resistance (MDR) is a major contributor to death in colorectal carcinoma (CRC). Here, we investigated the possible role of microRNA (miR)-503-5p in drug resistant CRC cells. Unbiased microRNA array screening revealed that miR-503-5p is up-regulated in two oxaliplatin (OXA)-resistant CRC cell lines. Overexpression of miR-503-5p conferred resistance to OXA-induced apoptosis and inhibition of tumor growth in vitro and in vivo through down-regulation of PUMA expression. miR-503-5p knockdown sensitized chemoresistant CRC cells to OXA. Our studies indicated that p53 suppresses miR-503-5p expression and that deletion of p53 upregulates miR-503-5p expression. Inhibition of miR-503-5p in p53 null cells increased their sensitivity to OXA treatment. Importantly, analysis of patient samples showed that expression of miR-503-5p negatively correlates with PUMA in CRC. These results indicate that a p53/miR-503-5p/PUMA signaling axis regulates the CRC response to chemotherapy, and suggest that miR-503-5p plays an important role in the development of MDR in CRC by modulating PUMA expression.