microRNA-1827 represses MDM2 to positively regulate tumor suppressor p53 and suppress tumorigenesis
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Cen Zhang1, Juan Liu1, Chunwen Tan2, Xuetian Yue1, Yuhan Zhao1, Jiaping Peng2, Xiaolong Wang1, Saurabh V. Laddha3, Chang S. Chan3, Shu Zheng2, Wenwei Hu1,4, Zhaohui Feng1,4
1Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA
2Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China
3Center for Systems Biology, Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, New Brunswick, NJ 08903, USA
4Department of Pharmacology, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA
Wenwei Hu, e-mail: firstname.lastname@example.org
Zhaohui Feng, e-mail: email@example.com
Keywords: tumor suppressor, p53, MDM2, negative feedback loop, microRNA
Received: October 07, 2015 Accepted: January 15, 2016 Published: January 30, 2016
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.
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