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.
Highlights
The intestinal mucosal surface area represents the most significant anatomic and physiologic portal for systemic exposure to environmental toxins and microorganisms [1]
Similar to human colon cancer tissue [25], the Spint1 mRNA level was essentially preserved in ApcMin/þ tumor tissue (Fig. 1B), suggesting that the decreased immunoreactivity may be caused by enhanced shedding of membrane-bound Hai-1/Spint1 from the neoplastic cell surface
Given that hepatocyte growth factor activator inhibitor (HAI)-1 shedding is reported to be mediated by metalloprotease activity [29] and in human oral carcinoma cells MT1-MMP/MMP14 is responsible for HAI type 1 (HAI-1)/serine protease inhibitor Kunitz type 1 (SPINT1) ectodomain shedding [30], we compared Mmp14 expression in tumor tissue with corresponding normal mucosa in ApcMin/þ intestine and found that the Mmp14 mRNA level was significantly increased in tumor tissue (Fig. 1C)
Summary
The intestinal mucosal surface area represents the most significant anatomic and physiologic portal for systemic exposure to environmental toxins and microorganisms [1]. The systemic compartment is protected from these exposures by the mucosal epithelial barrier, with barrier dysfunction contributing to local and systemic diseases including inflammatory bowel disease, allergic disorders and malignancies [1, 2]. Authors' Affiliations: 1Section of Oncopathology and Regenerative Biology, Department of Pathology, 2Section of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki; and 3Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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