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

被引：518

作者：

Cooks, Tomer ^{[1
]}

Pateras, Ioannis S. ^{[2
]}

Tarcic, Ohad ^{[1
]}

Solomon, Hilla ^{[1
]}

Schetter, Aaron J. ^{[3
]}

Wilder, Sylvia ^{[1
]}

Lozano, Guillermina ^{[4
]}

Pikarsky, Eli ^{[5
,6
]}

Forshew, Tim ^{[7
]}

Rozenfeld, Nitzan ^{[7
]}

Harpaz, Noam ^{[8
]}

Itzkowitz, Steven ^{[9
]}

Harris, Curtis C. ^{[3
]}

Rotter, Varda ^{[1
]}

Gorgoulis, Vassilis G. ^{[2
,10
]}

Oren, Moshe ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[2] Univ Athens, Sch Med, Mol Carcinogenesis Grp, Dept Histol Embryol, Athens 15771, Greece

[3] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[5] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Immunol & Canc Res, IL-91120 Jerusalem, Israel

[6] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Pathol, IL-91120 Jerusalem, Israel

[7] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England

[8] Mt Sinai Sch Med, Dept Pathol, New York, NY 10029 USA

[9] Mt Sinai Sch Med, Dept Med, Div Gastroenterol, New York, NY 10029 USA

[10] Acad Athens, Biomed Res Fdn, Athens 11527, Greece

来源：

CANCER CELL | 2013年 / 23卷 / 05期

基金：

以色列科学基金会;

关键词：

COLITIS-ASSOCIATED NEOPLASIA; ULCERATIVE-COLITIS; MOUSE MODEL; TUMOR-SUPPRESSOR; MUTATIONS; CELLS; COLON; GAIN; GENE; EXPRESSION;

D O I：

10.1016/j.ccr.2013.03.022

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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-alpha-induced NF-kappa B 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-kappa B 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.

引用

页码：634 / 646

页数：13

共 59 条

[1]

Gain-of-function mutant p53 but not p53 deletion promotes head and neck cancer progression in response to oncogenic K-ras [J].