Abstract
Tumor suppressor p53 plays a central role in tumor suppression. To ensure its proper function, the levels and activity of p53 are under a tight regulation in cells. MicroRNAs are short non-coding RNAs that play an important role in regulation of gene expression. Recently, microRNA-339-5p has been reported to be frequently down-regulated in colorectal cancer, and furthermore, its down-regulation is associated with poor prognosis in cancer patients, which strongly suggests a tumor suppressive function of microRNA-339-5p in colorectal cancer. In this study, we found that microRNA-339-5p directly represses the expression of MDM2, a key negative regulator of p53, through binding to MDM2 3'-UTR in colorectal cancer cells. Through the down-regulation of MDM2, microRNA-339-5p increases p53 protein levels and functions, including p53 transcriptional activity and p53-mediated apoptosis and senescence in response to stress. Furthermore, microRNA-339-5p inhibits the migration and invasion of colorectal cancer cells and the growth of colorectal xenograft tumors in a largely p53-dependent manner. Our results highlighted an important role of microRNA-339-5p in suppression of colorectal tumorigenesis, and also revealed that regulating the p53 function is an important mechanism for microRNA-339-5p in tumor suppression.
Highlights
The tumor suppressor p53 and its signaling pathway play a central role in suppression of tumorigenesis, including colorectal cancer [1,2,3]
We found that miR339-5p directly represses MDM2 expression, which in turn increases p53 protein levels and enhances p53 functions in regulating apoptosis and senescence in colorectal cancer cells in response to stress
MiRNA-339-5p was reported to be frequently down-regulated in colorectal cancer, and its decreased expression is associated with poor prognosis in colorectal cancer patients, which strongly suggests a potential role of miR-339-5p in suppression of colorectal cancer [25]
Summary
The tumor suppressor p53 and its signaling pathway play a central role in suppression of tumorigenesis, including colorectal cancer [1,2,3]. P53 is activated and accumulated in cells, which in turn transcriptionally regulates many target genes to initiate various cellular responses to maintain genomic stability and prevent tumorigenesis, including apoptosis, cell cycle arrest and senescence [1,2,3]. To ensure its proper function in tumor suppression, the levels and activities of p53 are under a tight and complex regulation by many different regulators and mechanisms in cells [2, 5, 6]. MDM2 is frequently overexpressed in various types of tumors, including colorectal cancer, which attenuates p53 function and promotes tumorigenesis [9,10,11]
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