title: Deletion of p38-alpha mitogen-activated protein kinase within the intestinal epithelium promotes colon tumorigenesis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA.
authors: Derek
authors: D
authors: Wakeman
authors: John E
authors: JE
authors: Schneider
authors: Jingxia
authors: J
authors: Liu
authors: Wambul S
authors: WS
authors: Wandu
authors: Christopher R
authors: CR
authors: Erwin
authors: Jun
authors: J
authors: Guo
authors: Thaddeus S
authors: TS
authors: Stappenbeck
authors: Brad W
authors: BW
authors: Warner
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology; D003106:Colon / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D016264:Dextran Sulfate; D020895:Enterocytes / Q000201:enzymology; D005243:Feces; D007413:Intestinal Mucosa / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D015431:Weight Loss
chemical_list: D002273:Carcinogens; D016264:Dextran Sulfate; D048308:Mitogen-Activated Protein Kinase 14; D001397:Azoxymethane