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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 expression is downregulated in human colon adenomas and adenocarcinomasExpression of ST14, encoding matriptase, in 14 gene expression array studies of human colon adenomas and adenocarcinomas. Data are expressed as fold change relative to corresponding normal tissue. *P<0.05, **P<0.01, ***P<0.001. See Supplementary Table 1 for details and references.
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Figure 1: Matriptase expression is downregulated in human colon adenomas and adenocarcinomasExpression of ST14, encoding matriptase, in 14 gene expression array studies of human colon adenomas and adenocarcinomas. Data are expressed as fold change relative to corresponding normal tissue. *P<0.05, **P<0.01, ***P<0.001. See Supplementary Table 1 for details and references.

Mentions: We first performed in silico data mining of the Oncomine microarray database (Rhodes et al., 2004) to corroborate the initial report of reduced ST14 expression in human colon cancer (Zhang et al., 1998) (Figure 1). Interestingly, ST14 was significantly downregulated compared to normal colon in seven of the fourteen published studies listed in the database (studies A and C–H), whereas six studies showed no change (studies B and J–N) and a single study (study I) found ST14 to be upregulated (Figure 1 and Supplementary Table 1). Of the fourteen studies, study A, which compared gene expression in colorectal dysplastic adenomatous polyps to normal colonic epithelium, was conducted using laser capture microdissected tissue (ST14 downregulation, P < 0.0006) (Gaspar et al., 2008), and therefore provided the most reliable estimate of ST14 expression in normal and dysplastic colonic epithelium.


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 expression is downregulated in human colon adenomas and adenocarcinomasExpression of ST14, encoding matriptase, in 14 gene expression array studies of human colon adenomas and adenocarcinomas. Data are expressed as fold change relative to corresponding normal tissue. *P<0.05, **P<0.01, ***P<0.001. See Supplementary Table 1 for details and references.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3299858&req=5

Figure 1: Matriptase expression is downregulated in human colon adenomas and adenocarcinomasExpression of ST14, encoding matriptase, in 14 gene expression array studies of human colon adenomas and adenocarcinomas. Data are expressed as fold change relative to corresponding normal tissue. *P<0.05, **P<0.01, ***P<0.001. See Supplementary Table 1 for details and references.
Mentions: We first performed in silico data mining of the Oncomine microarray database (Rhodes et al., 2004) to corroborate the initial report of reduced ST14 expression in human colon cancer (Zhang et al., 1998) (Figure 1). Interestingly, ST14 was significantly downregulated compared to normal colon in seven of the fourteen published studies listed in the database (studies A and C–H), whereas six studies showed no change (studies B and J–N) and a single study (study I) found ST14 to be upregulated (Figure 1 and Supplementary Table 1). Of the fourteen studies, study A, which compared gene expression in colorectal dysplastic adenomatous polyps to normal colonic epithelium, was conducted using laser capture microdissected tissue (ST14 downregulation, P < 0.0006) (Gaspar et al., 2008), and therefore provided the most reliable estimate of ST14 expression in normal and dysplastic colonic epithelium.

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