title: Hepatocyte growth factor activator inhibitor type 1 is a suppressor of intestinal tumorigenesis.
abstract: Hepatocyte growth factor activator inhibitor type 1 (HAI-1/SPINT1) is a membrane-bound serine protease inhibitor expressed on the surface of epithelial cells. Although HAI-1/SPINT1 is abundantly expressed in the intestinal epithelium, its role in intestinal tumorigenesis is not known. In this study, we investigated the role of Hai-1/Spint1 in intestinal tumorigenesis using mouse models. The membranous Hai-1/Spint1 immunoreactivity was decreased in murine Apc(Min/+) tumors and also in carcinogen (azoxymethane treatment followed by dextran sodium sulfate administration)-induced colon tumors compared with the adjacent non-neoplastic epithelium. The decreased immunoreactivity appeared to be due to sheddase activity of membrane-type 1 matrix metalloprotease. Then, we examined the effect of intestine-specific deletion of Spint1 gene on Apc(Min/+) mice. The loss of Hai-1/Spint1 significantly accelerated tumor formation in Apc(Min/+) mice and shortened their survival periods. Activation of HGF was enhanced in Hai-1/Spint1-deficient Apc(Min/+) intestine. Gene expression profiling revealed upregulation of the Wnt/β-catenin signaling circuit, claudin-2 expression, and angiogenesis not only in tumor tissue but also in the background mucosa without macroscopic tumors in Hai-1/Spint1-deficient Apc(Min/+) intestine. Intestinal deletion of Spint1 also enhanced the susceptibility to carcinogen-induced colon tumorigenicity of wild-type Apc mice. Our findings suggest that HAI-1/SPINT1 has a crucial role in suppressing intestinal tumorigenesis, which implies a novel link between epithelial cell surface serine protease inhibitors and protection from carcinogenic stimuli.
authors: Authors' Affiliations: Section of Oncopathology and Regenerative Biology, Department of Pathology, Section of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki; and Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors: Shinri
authors: S
authors: Hoshiko
authors: Makiko
authors: M
authors: Kawaguchi
authors: Tsuyoshi
authors: T
authors: Fukushima
authors: Yukihiro
authors: Y
authors: Haruyama
authors: Kenji
authors: K
authors: Yorita
authors: Hiroyuki
authors: H
authors: Tanaka
authors: Motoharu
authors: M
authors: Seiki
authors: Haruhiko
authors: H
authors: Inatsu
authors: Kazuo
authors: K
authors: Kitamura
authors: Hiroaki
authors: H
authors: Kataoka
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D010539:Permeability; D053491:Proteinase Inhibitory Proteins, Secretory; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D002273:Carcinogens; D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C504591:Spint1 protein, mouse; D025521:Tumor Suppressor Proteins; D017228:Hepatocyte Growth Factor