Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans

Mohammed Soutto, Abbes Belkhiri, M. Blanca Piazuelo, Barbara G. Schneider, Dunfa Peng, Aixiang Jiang, M. Kay Washington, Yasin Kokoye, Sheila E. Crowe, Alexander Zaika, Pelayo Correa, Richard M. Peek, Wael El-Rifai

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1753-1767
Number of pages15
JournalJournal of Clinical Investigation
Volume121
Issue number5
DOIs
StatePublished - May 2 2011
Externally publishedYes

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Stomach
Inflammation
Neoplasms
Knockout Mice
Carcinogenesis
I-kappa B Kinase
Pyloric Antrum
Peptides
Tumor Necrosis Factor Receptors
Gastritis
Gastric Mucosa
Tumor Suppressor Genes
Hyperplasia
Histology
Adenocarcinoma
Peptide Hydrolases
Transcription Factors
Trefoil Factor-1
Carcinoma
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans. / Soutto, Mohammed; Belkhiri, Abbes; Piazuelo, M. Blanca; Schneider, Barbara G.; Peng, Dunfa; Jiang, Aixiang; Washington, M. Kay; Kokoye, Yasin; Crowe, Sheila E.; Zaika, Alexander; Correa, Pelayo; Peek, Richard M.; El-Rifai, Wael.

In: Journal of Clinical Investigation, Vol. 121, No. 5, 02.05.2011, p. 1753-1767.

Research output: Contribution to journalArticle

Soutto, M, Belkhiri, A, Piazuelo, MB, Schneider, BG, Peng, D, Jiang, A, Washington, MK, Kokoye, Y, Crowe, SE, Zaika, A, Correa, P, Peek, RM & El-Rifai, W 2011, 'Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans', Journal of Clinical Investigation, vol. 121, no. 5, pp. 1753-1767. https://doi.org/10.1172/JCI43922
Soutto, Mohammed ; Belkhiri, Abbes ; Piazuelo, M. Blanca ; Schneider, Barbara G. ; Peng, Dunfa ; Jiang, Aixiang ; Washington, M. Kay ; Kokoye, Yasin ; Crowe, Sheila E. ; Zaika, Alexander ; Correa, Pelayo ; Peek, Richard M. ; El-Rifai, Wael. / Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 5. pp. 1753-1767.
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