Role of intestinal trefoil factor in gastric carcinogenesis

The aim of this project was to define the role of ITF in gastric carcinogenesis. The thesis consisted of two parts of scientific studies to investigate the effects of: inducing ITF expression on the proliferation and invasion of non-tumorigenic rat fbroblast cells (Part 1) and silencing ITF on the proliferation, angiogenesis and chemotherapeutic response in gastric cancer cells (Part 2).Induction of ITF expression significantly enhanced invasion of Rat-2 (1.8-folds) without promoting proliferation. The increase in invasiveness was accompanied by an upregulation of beta-catenin (18.0%) and MMP-9 (67.8%), and downregulation of E-cadherin (29.7%) and TIMP-1 (34.7%). Silencing ITF in MKN45 markedly delayed the onset of tumor progression by Day 6 and reduced the tumor volume by 85% by Day 14. ITF siRNA significantly attenuated angiogenesis in vivo and in vitro. The effects of silencing ITF were mediated through transcriptional upregulation of the Bax (114%), Bak (89%), Ang-2 (89%) and Tie-2 (399%). Bcl-2, Bcl-xL, VEGF and Ang-1 expressions were not significantly altered. Silencing ITF in gastric cancer cells increased the effect of cisplatin-induced apoptosis in a dose-dependent manner.Our findings suggested that ITF plays a role in invasion, proliferation and angiogenesis. The mechanisms involve regulation of catenin-cadherin complexes, balance of MMPs/TIMPs, proapoptotic Bcl-2 family members and Ang-2/Tie-2 system. Silencing ITF enhanced the chemotherapeutic response of gastric cancer cells to cisplatin. Blocking ITF expression using RNA interference may have a potential therapeutic application in gastric cancer. (Abstract shortened by UMI.)...