title: Suppression of Tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis.
abstract: Colitis-associated colorectal cancers are an etiologically distinct subgroup of colon cancers that occur in individuals suffering from inflammatory bowel disease and arise as a consequence of persistent exposure of hyperproliferative epithelial stem cells to an inflammatory microenvironment. An intrinsic defect in the intestinal epithelial barrier has been proposed to be one of several factors that contribute to the inappropriate immune response to the commensal microbiota that underlies inflammatory bowel disease. Matriptase is a membrane-anchored serine protease encoded by Suppression of Tumorigenicity-14 (ST14) that strengthens the intestinal epithelial barrier by promoting tight junction formation. Here, we show that intestinal epithelial-specific ablation of St14 in mice causes formation of colon adenocarcinoma with very early onset and high penetrance. Neoplastic progression is preceded by a chronic inflammation of the colon that resembles human inflammatory bowel disease and is promoted by the commensal microbiota. This study demonstrates that inflammation-associated colon carcinogenesis can be initiated and promoted solely by an intrinsic intestinal permeability barrier perturbation, establishes St14 as a critical tumor-suppressor gene in the mouse gastrointestinal tract and adds matriptase to the expanding list of pericellular proteases with tumor-suppressive functions.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kosa
authors.forename: R
authors.initials: R
authors.lastname: Szabo
authors.forename: A A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: T H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000236:Adenoma / Q000201:enzymology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001485:Basement Membrane / Q000201:enzymology / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003092:Colitis / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology; D004848:Epithelium / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D007408:Intestinal Absorption; D008565:Membrane Proteins; D054892:Metagenome / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D011230:Precancerous Conditions; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008565:Membrane Proteins; D051176:beta Catenin; D012697:Serine Endopeptidases; C118992:St14 protein, mouse