Abstract 915: Serine protease inhibitor Kazal type 1 promote a carcinogenesis of the colon
Authors: Satoshi Ida, Masaki Ohmuraya, Masaaki Iwatsuki, Naoko Hayashi, Kei Horino, Masayuki Watanabe, Hiroshi Takamori, Tooru Beppu, Hideo Baba
Journal: Cancer Research (2011)

Abstract Colorectal cancer (CRC) is one of the most serious complications of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease. Although it is clear that the chronic inflammation is a risk factor of CRC, the pathogenesis of IBD-related CRC is still uncertain. Serine protease inhibitor Kazal type 1 (SPINK1: mouse homolog Spink3), which is also known as tumor associated trypsin inhibitor (TATI), is mainly produced in the pancreatic acinar cells. Although the role of SPINK1 has been postulated to be the prevention of inadvertent proteolysis in the pancreas caused by intra-acinar premature activation of trypsinogen, it is expressed in a various cancers, including colon cancer. In the colon cancer, previous reports said high expression of SPINK1 correlates with metastasis and poor prognosis. However, the role of SPINK1 in malignant tumors remains to be elucidated. Recently, we showed that SPINK1 overexpress in the chronic pancreatitis and pancreatic cancer. Furthermore, we showed that SPINK1 binds to epidermal growth factor receptor (EGFR) to activate its downstream signaling; resulting in proliferation of pancreatic and breast cancer cells. Hence, we hypothesized that SPINK1 plays a role as the growth factor for tissue repair in the inflammatory state, and if prolonged, it works to carcinogenesis in the colon tissue. We first showed that SPINK1 induced proliferation of colon cancer cell lines examined. To clarify the role in the colon cancer of SPINK1 in vivo, we used an efficient animal model for IBD-related colon carcinogenesis. Male C57BL/6 mice were given a single intraperitoneal administration of azoxymethane (AOM), followed by a 1-week oral exposure to dextran sodium sulfate (DSS). We showed that expression of EGFR and Spink3 were observed in DSS induced colitis state. Twelve weeks after injected AOM, multiple colon cancer occurred in all treated mice. In the western blotting, EGFR and Spink3 were overexpressed in the cancerous tissues. To determine whether Spink3 has an essential role of carcinogenesis, we further analyzed the tumor incidence of Spink3+/−mice. At 12 weeks, tumor number was 4.6 ± 0.8 (mean ± standard error) in Spink3+/+ mice and 1 ± 0.4 in Spink3+/− mice, and a significant difference was observed between the 2 groups (p&amp;lt;0.05). To further analyze the clinical importance of SPINK1 in the development of colon cancer, we examined the expression of SPINK1 and EGFR in adenoma and adenocarcinoma.SPINK1 express in adenoma and well differentiated adenocarcinoma, but not expressed in poorly differentiated adenocarcinoma. Taken together, these results suggest that SPINK1 stimulates the proliferation of colon cancer cells through the EGFR, and especially role in early carcinogenesis of IBD-related colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 915. doi:10.1158/1538-7445.AM2011-915