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In populations with similar prevalence of Helicobacter pylori infection, cancer risk can vary dramatically. Changes in composition or structure of bacterial communities in the stomach, either at the time of exposure or over the course of H. pylori infection, may contribute to gastric pathology. In this study, a population of 37 patients from the low-gastric-cancer-risk (LGCR) region of Tumaco, Colombia, and the high-gastric-cancer-risk (HGCR) region of Túquerres, Colombia, were recruited for gastric endoscopy. Antral biopsy specimens were processed for histology and bacterial isolation. Fifty-nine distinct species among 26 genera were isolated by aerobic, anaerobic, and microaerobic culture and confirmed by 16S rRNA analysis. Urease-positive Staphylococcus epidermidis and Streptococcus salivarius were frequently isolated from gastric biopsy specimens. We asked whether coinfection of H. pylori with urease-positive

// 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.