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

Kosa P, Szabo R, Molinolo AA, Bugge TH - Oncogene (2011)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

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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Matriptase-ablated colon is leakyThe lumen of the colon and small intestine of weaning age St14+ and littermate St14−animals was injected with Sulfo-NHS-LC-Biotin in PBS (a,b,d,e) or PBS (c,f). After three min, the intestine was excised, sectioned, and stained for biotin (green). Nuclei were stained with 4,6-diamino-2-phenylindol (blue). Arrows in a, d, and e show biotin bound to the surface of the mucosa. Arrowheads in b and the inset in e show biotin labeling of the basolateral membrane of polarized epithelial cells. The diffusion of biotin into intercellular space was not observed in the normal colon or small intestine (a,d, also compare insets in d and e). Stars show biotin labeling of connective tissue of both matriptase-ablated colon (b) and small intestine (e). There was no signal for biotin in colon and small intestine (c,f) injected with PBS. Scale bar = 20 μm.
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Figure 5: Matriptase-ablated colon is leakyThe lumen of the colon and small intestine of weaning age St14+ and littermate St14−animals was injected with Sulfo-NHS-LC-Biotin in PBS (a,b,d,e) or PBS (c,f). After three min, the intestine was excised, sectioned, and stained for biotin (green). Nuclei were stained with 4,6-diamino-2-phenylindol (blue). Arrows in a, d, and e show biotin bound to the surface of the mucosa. Arrowheads in b and the inset in e show biotin labeling of the basolateral membrane of polarized epithelial cells. The diffusion of biotin into intercellular space was not observed in the normal colon or small intestine (a,d, also compare insets in d and e). Stars show biotin labeling of connective tissue of both matriptase-ablated colon (b) and small intestine (e). There was no signal for biotin in colon and small intestine (c,f) injected with PBS. Scale bar = 20 μm.

Mentions: We have previously shown that either reduced matriptase expression or global postnatal ablation of matriptase from all tissues results in impaired intestinal barrier function (Buzza et al., 2010, List et al., 2009), suggesting that this would also be a feature of mice with intestinal epithelial-specific embryonic deletion of matriptase. To examine colonic and small intestinal barrier function, we injected a reactive biotin tracer into the intestinal lumen of three week old St14− and littermate St14+ mice and followed the fate of the marker using fluorescent streptavidin. Compatible with an intact intestinal barrier function, the biotin marker decorated the surface of colonic crypts and villi of the small intestine, but did not penetrate into the tissue of St14+ mice (Figure 5a and d). In contrast, just three minutes after intraluminal biotin injection, the biotin tracer could be found on the basolateral membranes and on connective tissue cells of the colon and small intestine of St14− mice demonstrating a profound failure to establish a functional intestinal barrier (Figure 5b and e).


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

Kosa P, Szabo R, Molinolo AA, Bugge TH - Oncogene (2011)

Matriptase-ablated colon is leakyThe lumen of the colon and small intestine of weaning age St14+ and littermate St14−animals was injected with Sulfo-NHS-LC-Biotin in PBS (a,b,d,e) or PBS (c,f). After three min, the intestine was excised, sectioned, and stained for biotin (green). Nuclei were stained with 4,6-diamino-2-phenylindol (blue). Arrows in a, d, and e show biotin bound to the surface of the mucosa. Arrowheads in b and the inset in e show biotin labeling of the basolateral membrane of polarized epithelial cells. The diffusion of biotin into intercellular space was not observed in the normal colon or small intestine (a,d, also compare insets in d and e). Stars show biotin labeling of connective tissue of both matriptase-ablated colon (b) and small intestine (e). There was no signal for biotin in colon and small intestine (c,f) injected with PBS. Scale bar = 20 μm.
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Related In: Results  -  Collection

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Figure 5: Matriptase-ablated colon is leakyThe lumen of the colon and small intestine of weaning age St14+ and littermate St14−animals was injected with Sulfo-NHS-LC-Biotin in PBS (a,b,d,e) or PBS (c,f). After three min, the intestine was excised, sectioned, and stained for biotin (green). Nuclei were stained with 4,6-diamino-2-phenylindol (blue). Arrows in a, d, and e show biotin bound to the surface of the mucosa. Arrowheads in b and the inset in e show biotin labeling of the basolateral membrane of polarized epithelial cells. The diffusion of biotin into intercellular space was not observed in the normal colon or small intestine (a,d, also compare insets in d and e). Stars show biotin labeling of connective tissue of both matriptase-ablated colon (b) and small intestine (e). There was no signal for biotin in colon and small intestine (c,f) injected with PBS. Scale bar = 20 μm.
Mentions: We have previously shown that either reduced matriptase expression or global postnatal ablation of matriptase from all tissues results in impaired intestinal barrier function (Buzza et al., 2010, List et al., 2009), suggesting that this would also be a feature of mice with intestinal epithelial-specific embryonic deletion of matriptase. To examine colonic and small intestinal barrier function, we injected a reactive biotin tracer into the intestinal lumen of three week old St14− and littermate St14+ mice and followed the fate of the marker using fluorescent streptavidin. Compatible with an intact intestinal barrier function, the biotin marker decorated the surface of colonic crypts and villi of the small intestine, but did not penetrate into the tissue of St14+ mice (Figure 5a and d). In contrast, just three minutes after intraluminal biotin injection, the biotin tracer could be found on the basolateral membranes and on connective tissue cells of the colon and small intestine of St14− mice demonstrating a profound failure to establish a functional intestinal barrier (Figure 5b and e).

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

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.

Show MeSH
Related in: MedlinePlus