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

The tumor suppressor p53 is frequently mutated in human cancer

brain cell

Authors
Tomer Cooks, Ioannis S. Pateras, Ohad Tarcic, Hilla Solomon, Aaron J. Schetter, Sylvia Wilder, Guillermina Lozano, Eli Pikarsky, Tim Forshew, Nitzan Rozenfeld, Noam Harpaz, Steven Itzkowitz, Curtis C. Harris, Varda Rotter, Vassilis G. Gorgoulis, Moshe Oren

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.

Full Article

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