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

Cen Zhang, Juan Liu, Chunwen Tan, Xuetian Yue, Yuhan Zhao, Jiaping Peng, Xiaolong Wang, Saurabh V. Laddha, Chang S. Chan, Shu Zheng, Wenwei Hu, Zhaohui Feng

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8783-8796
Number of pages14
JournalOncotarget
Volume7
Issue number8
DOIs
StatePublished - Jan 1 2016

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All Science Journal Classification (ASJC) codes

  • Oncology

Keywords

  • MDM2
  • MicroRNA
  • Negative feedback loop
  • Tumor suppressor
  • p53

Cite this

Zhang, C., Liu, J., Tan, C., Yue, X., Zhao, Y., Peng, J., Wang, X., Laddha, S. V., Chan, C. S., Zheng, S., Hu, W., & Feng, Z. (2016). microRNA-1827 represses MDM2 to positively regulate tumor suppressor p53 and suppress tumorigenesis. Oncotarget, 7(8), 8783-8796. https://doi.org/10.18632/oncotarget.7088