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 ApcMin/þ 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/þ mice. The loss ofHai-1/Spint1 significantly accelerated tumor formation in Apc Min/þ mice and shortened their survival periods.Activation of HGF was enhanced in Hai-1/Spint1-deficient Apc Min/þ intestine. Gene expression profiling revealed upregulation of the Wnt/b-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 Apcintestine. 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. Cancer Res; 73(8); 2659-70. Ó2013 AACR.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-bound serine protease inhibitor expressed in epithelial tissues. Mutant mouse models revealed that HAI-1/SPINT1 is essential for placental labyrinth formation and is critically involved in regulating epidermal keratinization through interaction with its cognate cell surface protease, matriptase. HAI-1/SPINT1 is abundantly expressed in both human and mouse intestinal epithelium; therefore, we analyzed its role in intestinal function using mice with intestinal epithelial cell-specific deletion of Spint1 generated by interbreeding mice carrying Spint1 LoxP homozygous alleles with transgenic mice carrying the Cre recombinase gene controlled by the intestine-specific Villin promoter. Although the resulting mice had normal development and appearance, crypts in the proximal aspect of the colon, including the cecum, exhibited histologic abnormalities and increased apoptosis and epithelial cell turnover accompanied by increased intestinal permeability. Distended endoplasmic reticula were observed ultrastructurally in some crypt epithelial cells, indicative of endoplasmic reticular stress. To study the role of HAI-1/SPINT1 in mucosal injury, we induced colitis by adding dextran sodium sulfate to the drinking water. After dextran sodium sulfate treatment, intestine-specific HAI-1/SPINT1-deficient mice had more severe symptoms and a significantly lower survival rate relative to control mice. These results suggest that HAI-1/SPINT1 plays an important role in maintaining colonic epithelium integrity.

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A 64-year-old man diagnosed with advanced malignant peritoneal mesothelioma by laparoscopic biopsy was treated with systemic chemotherapy. The patient underwent first-line chemotherapy with pemetrexed plus cisplatin for 11 months, then second-line chemotherapy with gemcitabine plus vinorelbine for 6 months, and third-line chemotherapy with CPT-11 for 4 months. After third-line chemotherapy failed, he received palliative treatment. Although the tumor continued to grow, and he died 24 months after initiation of treatment, chemotherapy prolonged the survival time and improved his quality of life.

<p>PDF file - 25K, Organ weights, hematocrit and hemoglobin concentration in mice.</p>

<p>PDF file - 36K, Spint1 deletion-induced up- and down-regulated genes involved in angiogenesis in non-neoplastic small intestine of Apc-min mice.</p>

<p>PDF file - 33K, Spint1 deletion-induced up- and down-regulated genes involved in cellular responses to DNA damage/repair in non-neoplastic small intestine of Apc-min mice.</p>

<p>PDF file - 58K, Body weight gain of mice.</p>