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Suppression of Tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis

Oncogene volume 31, pages 3679–3695 (2012)Cite this article

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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.

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Acknowledgements

We thank Drs Jerrold M Ward, Robert D Cardiff and Stephen M Hewitt for pathology advice, Drs Vyomesh Patel and Kantima Leelahavanichkul for help with the array analysis, Dr Myrna Mandel for helicobacter testing, as well as Drs Silvio Gutkind and Mary Jo Danton for critically reviewing this manuscript. Histology was performed by Histoserv Inc. (Germantown, MD, USA). This study was supported by the NIDCR Intramural Research Program (THB).

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  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    P Kosa, R Szabo, A A Molinolo & T H Bugge

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Correspondence to T H Bugge.

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Kosa, P., Szabo, R., Molinolo, A. et al. Suppression of Tumorigenicity-14, encoding matriptase, is a critical suppressor of colitis and colitis-associated colon carcinogenesis. Oncogene 31, 3679–3695 (2012). https://doi.org/10.1038/onc.2011.545

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