Gain-of-function miRNA signature by mutant p53 associates with poor cancer outcome.

Yao Zhang,Ye Hu,Jie Xu,Jing-Yuan Fang

doi:10.18632/oncotarget.7090

Abstract

Missense mutation of p53 not only impairs its tumor suppression function, but also causes oncogenic gain of function (GOF). The molecular underpinning of mutant p53 (mutp53) GOF is not fully understood, especially for the potential roles of non-coding genes. Here we identify the microRNA expression profile (microRNAome) of mutp53 on Arg282 by controlled microarray experiments, and clarify the prognostic significance of mutp53-regulated miRNAs in cancers. A predominant repression effect on miRNA expression was found for mutant p53, with 183 significantly downregulated and only 12 upregulated miRNAs. Mutp53 and wild-type (wtp53) commonly upregulate let-7i, and other two miRNAs were upregulated by wtp53 but repressed by mutp53 (miR-610 and miR-3065–3p). Based the mutp53-regulated miRNA signature, a non-negative matrix factorization (NMF) model classified gastric cancer (GC) cases into subgroups with significantly different Disease-free survival (Kaplan-Meier test, P = 0.013). In contrast, the NMF model based on all miRNAs did not associate with cancer outcome. The mutp53 miRNA signature associated with the outcomes of breast cancer (P = 0.024) and hepatocellular cancer (P = 0.012). The miRPath analysis revealed that mutp53-suppressed miRNAs associate with Hippo, TGF-β and stem cell signaling pathways. Taken together, our results highlight a miRNA-mediated GOF mechanism of mutant p53 on Arg282, and suggest the prognostic potential of mutp53-associated miRNA signature.

Highlights

The TP53 gene that encodes the p53 tumor suppressor protein is the most commonly mutated gene in all human cancers [1], and missense mutation causing substitution of single amino acid represents the major type of mutations of TP53 gene [2]
The mechanisms of mutp53 gain-of-function effect are important for developing targeted therapies against advanced cancers, and our study presents the first unbiased characterization of mutp53 R282W-regulated miRNAs
We demonstrate that a mutp53 miRNA signature can identify cancer subgroups with significantly different outcomes, and the hippo signaling is associated with the mutp53 signature

Summary

Introduction

The TP53 gene that encodes the p53 tumor suppressor protein is the most commonly mutated gene in all human cancers [1], and missense mutation causing substitution of single amino acid represents the major type of mutations of TP53 gene [2]. The wild-type p53 is a master regulator of human genomic integrity [3], which is stabilized an accumulated in the nucleus in response to genomic stress or oncogenic signaling [4]. The downstream target genes of p53 are involved in multiple pathways such as cell cycle arrest, apoptosis, and metabolism [6]. The cytoplasmic function of p53 protein associates with mitochondria outer membrane, where it binds BCL-XL and induces cytochrome C release and initiates apoptosis [7]

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