Abstract 3116: Serine protease inhibitor Kazal type 1 plays a role of colon carcinogenesis through the epidermal growth factor receptor

Abstract

Abstract 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 acinar cells. 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. SPINK1 is expressed not only in normal human pancreatic acinar cells, but also 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. We previously demonstrated that SPINK1/Spink3 can bind to EGFR and work as a growth factor through EGFR in the pancreatic cancer, even the chronic pancreatitis. 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 use an efficient animal model for colitis-related 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 (its ligand) were observed in DSS induced colitis state. Sixteen weeks after injected AOM, multiple colon cancer occurred in all treated mice. In the Western blot, EGFR and Spink3 overexpressed in the whole colon tissue (cancer tissue and non-cancerous lesion), but Spink3 slightly decreased in the cancer. To determine whether Spink3 has an essential role of carcinogenesis, we further analyzed the tumor incidence of Spink3+/−mice. At 16 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<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 in colon cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3116.