title: Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis.
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.
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.|Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soutto
authors.affiliation: Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.affiliation: Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Krishna
authors.affiliation: Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.affiliation: Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.|Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D021581:Active Transport, Cell Nucleus; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D014162:Transfection; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D010455:Peptides; D012333:RNA, Messenger; C051838:TFF1 protein, human; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D051176:beta Catenin
keywords: Helicobacter pylori; TFF1; gastric cancer; ß-catenin