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

被引:61
作者
Soutto, Mohammed [1 ,2 ]
Chen, Zheng [1 ,2 ]
Bhat, Ajaz A. [2 ,3 ]
Wang, Lihong [4 ]
Zhu, Shoumin [2 ]
Gomaa, Ahmed [2 ]
Bates, Andreia [4 ]
Bhat, Nadeem S. [2 ]
Peng, Dunfa [2 ]
Belkhiri, Abbes [4 ]
Piazuelo, M. Blanca [5 ]
Washington, M. Kay [6 ]
Steven, Xi Chen [7 ]
Peek, Richard, Jr. [5 ]
El-Rifai, Wael [1 ,2 ,8 ]
机构
[1] Miami Healthcare Syst, Dept Vet Affairs, Miami, FL 33125 USA
[2] Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA
[3] Sidra Med, Div Translat Med, Res Branch, Doha, Qatar
[4] Vanderbilt Univ, Dept Surg, Med Ctr, Nashville, TN 37240 USA
[5] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA
[6] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA
[7] Univ Miami, Miller Sch Med, Dept Publ Hlth Sci, Div Biostat, Miami, FL 33136 USA
[8] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; TREFOIL PROTEIN TFF1; HELICOBACTER-PYLORI; INFLAMMATION; CANCER; TUMORIGENESIS; TRANSCRIPTION; EXPRESSION; IL-6; METHYLATION;
D O I
10.1038/s41467-019-11011-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-STAT(Y705), 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-STAT3(Y705) expression. Reconstitution of TFF1 inhibits IL6-induced STAT3 transcription activity, suppressing expression of its target genes. TFF1 blocks IL6R alpha-GP130 complex formation through interfering with binding of IL6 to its receptor IL6R alpha. These findings demonstrate a functional role of TFF1 in suppressing gastric tumorigenesis by impeding the IL6-STAT3 pro-inflammatory signaling axis.
引用
收藏
页数:15
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