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Updated: May 20, 2026
In vitro Organoid Culture of Primary Mouse Colon Tumors
Published on: May 17, 2013
Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis
Derek Wakeman1, John E Schneider, Jingxia Liu
1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.
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.
Insights
Deleting p38-Alpha mitogen-activated protein kinase (p38-MAPK) in the intestine increased colon tumor development and burden. This suggests p38-MAPK may be a target for colorectal cancer prevention, especially with inflammatory bowel disease.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- p38-Alpha mitogen-activated protein kinase (p38-MAPK) is a tumor suppressor frequently mutated in human cancers.
- Its precise function in colorectal cancer (CRC) remains unclear, though prior research indicates it inhibits intestinal epithelial proliferation and promotes apoptosis.
- This study investigated the hypothesis that disrupting p38-MAPK in the intestine would enhance colon tumorigenesis.
Purpose of the Study:
- To determine the role of intestinal p38-MAPK in colorectal cancer development.
- To test if deleting p38-MAPK in the intestinal epithelium increases susceptibility to chemically induced tumors.
- To explore potential therapeutic strategies targeting p38-MAPK for CRC management.
Main Methods:
- Utilized a tamoxifen-inducible Cre-lox system to specifically delete p38-MAPK (MAPK14) in the intestinal epithelium of mice (villin-Cre ERT2(+), MAPK14(f/f)).
- Induced intestinal tumor development using a combined azoxymethane and dextran sodium sulfate (DSS) protocol.
- Quantified tumor number and size from excised colon specimens using imaging software.
Main Results:
- While the overall incidence of tumor-bearing mice did not differ significantly between wild-type and p38-MAPK-deleted groups (P = .21).
- Mice with intestinal epithelial p38-MAPK deletion exhibited a significantly higher number of tumors (3.7 vs 1.1; P = .008) and a fourfold increase in total tumor burden (17.4 vs 4.8 mm²; P = .03).
- Colon inflammation severity was comparable between both groups, suggesting tumor development was independent of augmented colitis.
Conclusions:
- Loss of p38-MAPK in the colonic mucosa promotes a hyperplastic state, leading to increased tumor development.
- The heightened tumorigenesis in p38-MAPK-deficient mice, without increased colitis, points to impaired cell cycle regulation in the colonic epithelium as the likely mechanism.
- Targeting p38-MAPK activity could represent a novel therapeutic or preventive approach for colorectal cancer, particularly in patients with inflammatory bowel disease.
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