title: Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.
abstract: BACKGROUND
  Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections.
  
  
  METHODS
  For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1.
  
  
  RESULTS
  The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice.
  
  
  CONCLUSIONS
  These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee.|Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soutto
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Katsha
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Uma S
authors.initials: US
authors.lastname: Krishna
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee.|Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Wael M
authors.initials: WM
authors.lastname: El-Rifai
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D054365:Chemokine CXCL5 / Q000276:immunology; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D016481:Helicobacter Infections / Q000235:genetics* / Q000276:immunology; D016480:Helicobacter pylori; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D066298:In Vitro Techniques; D007249:Inflammation; D053583:Interleukin-1beta / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics*; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D019948:Receptors, Interleukin-4 / Q000276:immunology; D013270:Stomach / Q000276:immunology / Q000382:microbiology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000276:immunology / Q000382:microbiology; D051996:Transcription Factor RelA / Q000378:metabolism; D000071163:Trefoil Factor-1; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D054365:Chemokine CXCL5; D053583:Interleukin-1beta; D010455:Peptides; D019948:Receptors, Interleukin-4; C472724:Tff1 protein, mouse; D051996:Transcription Factor RelA; D000071163:Trefoil Factor-1; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase
keywords: Helicobacter pylori; gastric cancer; inflammation; nuclear factor κB (NF-κB); trefoil factor 1 (TFF1)