title: Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans.
abstract: Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-α-mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-κB transcription factors and is an important event in shaping the NF-κB-mediated inflammatory response during the progression to gastric tumorigenesis.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soutto
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.forename: M Blanca
authors.initials: MB
authors.lastname: Piazuelo
authors.forename: Barbara G
authors.initials: BG
authors.lastname: Schneider
authors.forename: Dunfa
authors.initials: D
authors.lastname: Peng
authors.forename: Aixiang
authors.initials: A
authors.lastname: Jiang
authors.forename: M Kay
authors.initials: MK
authors.lastname: Washington
authors.forename: Yasin
authors.initials: Y
authors.lastname: Kokoye
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Crowe
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaika
authors.forename: Pelayo
authors.initials: P
authors.lastname: Correa
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000818:Animals; D018450:Disease Progression; D005753:Gastric Mucosa / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D013274:Stomach Neoplasms / Q000378:metabolism*; D000071163:Trefoil Factor-1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D010455:Peptides; C051838:TFF1 protein, human; C472724:Tff1 protein, mouse; D000071163:Trefoil Factor-1; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha