Work

Functional consequence of the p53 codon 72 polymorphism in colorectal cancer

Year: 2017

Type: article

Abstract: // Venkat R. Katkoori 1 , Upender Manne 2 , Lakshmi S. Chaturvedi 3 , Marc D. Basson 3 , Pam Haan 1 , Daniel Coffey 4 and Harvey L. Bumpers 1 1 Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA 2 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA 3 Department of Surgery, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND, USA 4 Capital Colorectal Surgery, Lansing, MI, USA Correspondence to: Harvey L. Bumpers, email: [email protected] Keywords: p53, codon 72 polymorphism, p38MAPK, EMT, CREB Received: May 23, 2017 Accepted: August 16, 2017 Published: August 29, 2017 ABSTRACT Background: The codon 72 polymorphism in p53 has been implicated in colorectal cancer (CRC) risk, prognosis and CRC health disparities. We examined the functional consequence of this polymorphism in CRC. Experimental Design: Plasmids (pCMV6) that express different phenotypes of p53 [p53 wild type (wt) at codon 72 (R72 wt ), R72 wt with mutation at codon 273 cysteine (R72 273Cys ), p53 mutation at codon 72 (P72 wt ) and P72 wt with mutation at codon 273 (P72 273Cys )] were constructed. The CRC cell line Caco2, which does not express p53 for in vitro studies, was used as host. CRC xenografts were established in severe combined immunodeficient (SCID) mice using established cell lines. CRC surgical specimens, corresponding normal colon, and tumor xenografts were sequenced for codon 72 polymorphism of p53. Proteins signaling mechanisms were evaluated to assess the functional consequence of P72 phenotype of p53. Results: This study demonstrated a significantly increased survival of cells expressing P72 wt , mutant phenotype, versus R72 wt phenotype. WB analyses revealed that P72 wt induced activation of p38 and RAF/MEK/ extracellular signal-regulated kinase (ERK) MAP kinases. Activation of CREB was found to be higher in tumors that exhibit P72 phenotype. Metastatic lesions of CRC expressed more phospho-CREB than non-metastatic lesions. The expression of P72 wt promoted CRC metastasis. Conclusions: P72 contributes to the aggressiveness of CRC. Because P72 is over-expressed in CRC, specifically in African-American patients, this suggests a role for P72 in cancer health disparities. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251 & U54CA118948.

Source: Oncotarget

DOI: 10.18632/oncotarget.20580