Mutant p53 Prolongs NF-κB Activation and Promotes Chronic Inflammation and Inflammation-Associated Colorectal Cancer

Cancer Cell. 2013 May 13;23(5):634-46. doi: 10.1016/j.ccr.2013.03.022.

Abstract

The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-α-induced NF-κB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-κB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azoxymethane
  • Colitis / chemically induced
  • Colitis / complications
  • Colitis / genetics
  • Colon / metabolism
  • Colon / pathology
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • DNA Damage
  • Dextran Sulfate
  • Genetic Predisposition to Disease
  • Histones / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Isoforms / physiology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / physiology
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Histones
  • NF-kappa B
  • Protein Isoforms
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • gamma-H2AX protein, mouse
  • Dextran Sulfate
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Azoxymethane

Associated data

  • GEO/GSE43738