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Background & Aims: Intestinal trefoil factor (ITF) has a role in gastrointestinal mucosal integrity and the repair of damaged mucosa. However, little is known about its role in tumors. To analyze the role of ITF in colon carcinomas, overexpression of the ITF gene in colon carcinoma cells was used. Methods: Human colon carcinoma cell lines LoVo and SW837, expressing no endogenous ITF, and WiDr expressing a low level of ITF were stably transfected with an expression vector harboring human ITF complementary DNA. The effects of ITF overexpression on in vitro growth, morphology in collagen gel, response to epidermal growth factor (EGF), mitogen-activated protein kinase (MAPK) activity, and growth in nude mice were assessed. Results: Overexpression of ITF in LoVo and SW837 resulted in significantly reduced growth in vitro and in vivo. In collagen gels, the ITF-expressing LoVo clones formed smaller, more dispersed colonies. EGF-induced phosphorylation of MAPKs was modestly reduced in the ITF-expressing clones. The growth of WiDr was modestly suppressed only in vivo by ITF overexpression. Conclusions: Overexpression of ITF suppressed the growth of colon carcinoma cells. ITF may function as an inhibitory factor for the growth of colonic neoplasm. GASTROENTEROLOGY 2000;118:60-69