microRNA-1827 represses MDM2 to positively regulate tumor suppressor p53 and suppress tumorigenesis

Abstract

// Cen Zhang 1 , Juan Liu 1 , Chunwen Tan 2 , Xuetian Yue 1 , Yuhan Zhao 1 , Jiaping Peng 2 , Xiaolong Wang 1 , Saurabh V. Laddha 3 , Chang S. Chan 3 , Shu Zheng 2 , Wenwei Hu 1, 4 , Zhaohui Feng 1, 4 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA 2 Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China 3 Center for Systems Biology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA 4 Department of Pharmacology, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA Correspondence to: Wenwei Hu, e-mail: wh221@cinj.rutgers.edu Zhaohui Feng, e-mail: fengzh@cinj.rutgers.edu Keywords: tumor suppressor, p53, MDM2, negative feedback loop, microRNA Received: October 07, 2015      Accepted: January 15, 2016      Published: January 30, 2016 ABSTRACT The tumor suppressor p53 plays a central role in tumor prevention. The E3 ubiquitin ligase MDM2 is the most critical negative regulator of p53, which binds to p53 and degrades p53 through ubiquitation. MDM2 itself is a transcriptional target of p53, and therefore, MDM2 forms a negative feedback loop with p53 to tightly regulate p53 levels and function. microRNAs (miRNAs) play a key role in regulation of gene expression. miRNA dysregulation plays an important role in tumorigenesis. In this study, we found that miRNA miR-1827 is a novel miRNA that targets MDM2 through binding to the 3′-UTR of MDM2 mRNA. miR-1827 negatively regulates MDM2, which in turn increases p53 protein levels to increase transcriptional activity of p53 and enhance p53-mediated stress responses, including apoptosis and senescence. Overexpression of miR-1827 suppresses the growth of xenograft colorectal tumors, whereas the miR-1827 inhibitor promotes tumor growth in mice in a largely p53-dependent manner. miR-1827 is frequently down-regulated in human colorectal cancer. Decreased miR-1827 expression is associated with high MDM2 expression and poor prognosis in colorectal cancer. In summary, our results reveal that miR-1827 is a novel miRNA that regulates p53 through targeting MDM2 , and highlight an important role and the underlying mechanism of miR-1827 in tumor suppression.