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, Dun Fa Peng, Aixiang Jiang, M. Kay Washington, Yasin Kokoye, Sheila E. Crowe, Alexander Zaika, Pelayo Correa, Richard M. Peek, Wael El-Rifai

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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

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ASJC Scopus subject areas

  • Medicine(all)

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Soutto, M., Belkhiri, A., Piazuelo, M. B., Schneider, B. G., Peng, D. F., Jiang, A., Washington, M. K., Kokoye, Y., Crowe, S. E., Zaika, A., Correa, P., Peek, R. M., & 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, 121(5), 1753-1767. https://doi.org/10.1172/JCI43922