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// Mohammed Soutto 1, 2 , Judith Romero-Gallo 3 , Uma Krishna 3 , M. Blanca Piazuelo 3 , M. Kay Washington 4 , Abbes Belkhiri 2 , Richard M. Peek Jr 3, 5 , Wael El-Rifai 1, 2, 5 1 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA 2 Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA 3 Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA 4 Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 5 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA Correspondence to: Wael El-Rifai, e-mail: wael.el-rifai@vanderbilt.edu Keywords: TFF1, Helicobacter pylori, s-catenin, gastric cancer Abbreviations: TFF1; trefoil factor 1, H. pylori; Helicobacter pylori, knockout; KO, TCF/LEF; T cell factor/lymphoid Received: February 18, 2015 Accepted: April 14, 2015 Published: April 27, 2015 ABSTRACT Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori -mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori -induced β-catenin nuclear translocation, as compared to control ( p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes ( CCND1 and c-MYC) , as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori -induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1 -KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1 -KO, as compared to Tff1 -WT mice ( p < 0.05). Only 10% of uninfected Tff1 -KO mice, as opposed to one-third of H. pylori -infected Tff1 -KO mice, developed invasive adenocarcinoma ( p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori -mediated oncogenic activation of β-catenin and gastric tumorigenesis.