Mutant p53-R273H gains new function in sustained activation of EGFR signaling via suppressing miR-27a expression

Abstract

p53 is a major tumor suppressor whose function is pivotal for protection against cancer. In over half of human cancers, p53 is inactivated due to either point mutation or loss of p53 gene. It has been well established that in addition to abrogating the tumorsuppressive function of wild-type p53, mutant p53 gains new functions and actively contributes to various stages of tumor progression. However, little is known about whether microRNA (miRNA) is involved in the gain-of-function of mutant p53. Here we report miR-27a as a novel downstream transcriptional target of mutant p53-273H. Mutant p53 binds to the miR-27a promoter region and suppresses its expression. We also identify epidermal growth factor receptor (EGFR) as a direct target of miR-27a. Via the miR-27a/EGFR axis, mutant p53-273H promotes a sustained EGF-induced extracellular signal-regulated kinase 1/2 activation, thereby facilitating cell proliferation and tumorigenesis. Collectively, this work reveals a direct link between the gainof-function of mutant p53 and miRNA and uncovers a novel mutant p53-273H/miR-27a/EGFR pathway that has an important role in promoting tumor development. © 2013 Macmillan Publishers Limited All rights reserved.