miR-503-5p confers drug resistance by targeting PUMA in colorectal carcinoma
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Ke Xu1,2,*, Guo Chen3,*, Yanyan Qiu1,2,4, Zeting Yuan1, Hongchang Li4, Xia Yuan5, Jian Sun1,2, Jianhua Xu2, Xin Liang6, Peihao Yin2,4
1Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
2Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Medicine, Shanghai 200062, PR China
3Department of Radiation Oncology, School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, USA
4Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China State
5Department of Pharmacy, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, PR China
6State 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
Peihao Yin, email: [email protected]
Ke Xu, email: [email protected]
Xin Liang, email: [email protected]
Keywords: colorectal carcinoma, multidrug-resistance, miR-503-5p, PUMA, p53
Received: August 24, 2016 Accepted: January 22, 2017 Published: February 21, 2017
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.
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