Differentially Regulated Micro-RNAs and Actively Translated Messenger RNA Transcripts by Tumor Suppressor p53 in Colon Cancer

Abstract

Purpose: The aim of this study was to investigate the role of p53 in regulating micro-RNA (miRNA) expression due to its function as a transcription factor. In addition, p53 may also affect other cellular mRNA gene expression at the translational level either via its mediated miRNAs or due to its RNA-binding function. Experimental Design: The possible interaction between p53 and miRNAs in regulating gene expression was investigated using human colon cancer HCT-116 (wt-p53) and HCT-116 (nullp53) cell lines. The effect of p53 on the expression of miRNAs was investigated using miRNA expression array and real-time quantitative reverse transcription-PCR analysis. Results: Our investigation indicated that the expression levels of a number of miRNAs were affected by wt-p53. Down-regulation of wt-p53 via small interfering RNA abolished the effect of wt-p53 in regulating miRNAs in HCT-116 (wt-p53) cells. Global sequence analysis revealed that over 46% of the 326 miRNA putative promoters contain potential p53-binding sites, suggesting that some of these miRNAs were potentially regulated directly by wt-p53. In addition, the expression levels of steady-state total mRNAs and actively translated mRNA transcripts were quantified by high-density microarray gene expression analysis. The results indicated that nearly 200 cellular mRNA transcripts were regulated at the posttranscriptional level, and sequence analysis revealed that some of these mRNAs may be potential targets of miRNAs, including translation initiation factor eIF-5A, eIF-4A, and protein phosphatase 1. Conclusion: To the best of our knowledge, this is the first report demonstrating that wt-p53 and miRNAs interact in influencing gene expression and providing insights of how p53 regulates genes at multiple levels via unique mechanisms.

Human papillomavirus type 16 reduces the expression of microRNA-218 in cervical carcinoma cells

“…Interestingly, SLIT2 is a possible target of miR-200c (overexpressed in the HPV-positive cell lines and tissues) (Supplementary Table 7). One study has shown that the absence of the p53 gene increases miR-200c expression (Xi et al, 2006). Thus, it is possible that E6-dependent degradation of the p53 protein results in miR-200c overexpression, which in turn reduces the levels of miR-218 and SLIT2 mRNA.…”

Tiny Actors, Great Roles: microRNAs in p53's Service

“…The first indication that p53 may influence the abundance of specific miRNAs was provided by Xi et al 38 Based on a comparison between HCT116 colorectal cancer cells and their derivatives in which the endogenous wild type p53 gene had been somatically knocked-out, these authors reported that p53 modulates the repertoire of polysome-associated miRNAs. Such effect might, in principle, be due either to p53-mediated regulation of miRNA expression, or to p53-mediated modulation of the association of particular miRNAs with the translational machinery.…”

Analysis of the immunohistochemical expressions of p53, bcl-2 and Ki-67 in colorectal adenocarcinoma and their correlations with the prognostic factors

“…Because of this function of detecting DNA abnormalities and consequent cell correction or death, the p53 protein is considered to be a genome guardian and is an important element in preventing tumor development. Its encoding gene is classified as a tumor suppressor gene (26,29) .…”