Activation of STAT3 signaling is mediated by TFF1 silencing in gastric neoplasia

Mohammed Soutto, Zheng Chen, Ajaz A. Bhat, Lihong Wang, Shoumin Zhu, Ahmed Gomaa, Andreia Bates, Nadeem S. Bhat, Dunfa Peng, Abbes Belkhiri, M. Blanca Piazuelo, M. Kay Washington, Xi Chen Steven, Richard Peek and Wael El-Rifai ()
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Mohammed Soutto: Miami Healthcare System
Zheng Chen: Miami Healthcare System
Ajaz A. Bhat: University of Miami Miller School of Medicine
Lihong Wang: Vanderbilt University Medical Center
Shoumin Zhu: University of Miami Miller School of Medicine
Ahmed Gomaa: University of Miami Miller School of Medicine
Andreia Bates: Vanderbilt University Medical Center
Nadeem S. Bhat: University of Miami Miller School of Medicine
Dunfa Peng: University of Miami Miller School of Medicine
Abbes Belkhiri: Vanderbilt University Medical Center
M. Blanca Piazuelo: Vanderbilt University Medical Center
M. Kay Washington: Vanderbilt University Medical Center
Xi Chen Steven: University of Miami Miller School of Medicine
Richard Peek: Vanderbilt University Medical Center
Wael El-Rifai: Miami Healthcare System

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract TFF1, a secreted protein, plays an essential role in keeping the integrity of gastric mucosa and its barrier function. Loss of TFF1 expression in the TFF1-knockout (KO) mouse leads to a pro-inflammatory phenotype with a cascade of gastric lesions that include low-grade dysplasia, high-grade dysplasia, and adenocarcinomas. In this study, we demonstrate nuclear localization of p-STATY705, with significant overexpression of several STAT3 target genes in gastric glands from the TFF1-KO mice. We also show frequent loss of TFF1 with nuclear localization of STAT3 in human gastric cancers. The reconstitution of TFF1 protein in human gastric cancer cells and 3D gastric glands organoids from TFF1-KO mice abrogates IL6-induced nuclear p-STAT3Y705 expression. Reconstitution of TFF1 inhibits IL6-induced STAT3 transcription activity, suppressing expression of its target genes. TFF1 blocks IL6Rα-GP130 complex formation through interfering with binding of IL6 to its receptor IL6Rα. These findings demonstrate a functional role of TFF1 in suppressing gastric tumorigenesis by impeding the IL6-STAT3 pro-inflammatory signaling axis.

Date: 2019
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DOI: 10.1038/s41467-019-11011-4

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