Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis

Derek Wakeman, John E. Schneider, Jingxia Liu, Wambul S. Wandu, Christopher R. Erwin, Jun Guo, Thaddeus S. Stappenbeck, Brad W. Warner

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Background: p38-Alpha mitogen-activated protein kinase (p38-MAPK) is a tumor suppressor often mutated in human cancers, but its specific role in colorectal cancer is not completely understood. Previous studies have found that p38-MAPK activity inhibits epithelial proliferation and promotes apoptosis in the intestine. Therefore, we sought to test the hypothesis that intestinal disruption of p38-MAPK would lead to increased tumorigenesis in the colon. Methods: p38-MAPK was deleted in mice within the intestinal epithelium using a tamoxifen-inducible Cre system under control of the villin promoter [villin-Cre ERT2(+), MAPK14(f/f)]. An azoxymethane and dextran sodium sulfate protocol was used to drive intestinal tumor development. Tumor measurements were made using computer software from photographs of excised colon specimens. Results: The number of mice that developed tumors was not statistically different when comparing wild-type mice (7/14) to inducible, intestine epithelial-deleted p38-MAPK (9/11) mice after azoxymethane/dextran sodium sulfate treatment (P =.21). However, the epithelial-deleted p38-MAPK mice developed significantly more tumors (3.7 vs 1.1; P =.008) and nearly 4 times the total tumor burden as wild-type mice (17.4 vs 4.8 mm 2; P =.03). Wild-type and epithelial-deleted p38-MAPK groups demonstrated a similar degree of colon inflammation. Conclusion: Deletion of p38-MAPK within the colonic mucosa leads to a hyperplastic state promoting greater tumor development. Because the severity of colitis was not augmented in mice with p38-MAPK deficiency, tumor development is likely mediated by impaired cell cycle regulation within the colonic epithelium. Manipulation of p38-MAPK activity may provide a novel treatment and/or prevention strategy in the management of colorectal cancer, particularly in the setting of inflammatory bowel disease.

Original languageEnglish
Pages (from-to)286-293
Number of pages8
JournalSurgery (United States)
Issue number2
StatePublished - Aug 2012


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