Priority Research Papers:
Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
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Mohammed Soutto1,2, Judith Romero-Gallo3, Uma Krishna3, M. Blanca Piazuelo3, M. Kay Washington4, Abbes Belkhiri2, Richard M. Peek Jr3,5, Wael El-Rifai1,2,5
1Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
2Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
3Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
4Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
5Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Wael El-Rifai, e-mail: email@example.com
Keywords: TFF1, Helicobacter pylori, ß-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
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.
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