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

Autor: Nadeem S. Bhat, Ahmed Gomaa, Andreia Bates, Xi Chen Steven, Dunfa Peng, Lihong Wang, Mohammed Soutto, Zheng Chen, Ajaz A. Bhat, M. Blanca Piazuelo, Wael El-Rifai, Richard M. Peek, M. Kay Washington, Abbes Belkhiri, Shoumin Zhu
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
General Physics and Astronomy
02 engineering and technology
medicine.disease_cause
Mice
Gastric glands
STAT3
lcsh:Science
Cancer
Mice
Knockout
Regulation of gene expression
Multidisciplinary
biology
Chemistry
Gastroenterology
021001 nanoscience & nanotechnology
Gene Expression Regulation
Neoplastic
Cell Transformation
Neoplastic
medicine.anatomical_structure
Trefoil Factor-1
0210 nano-technology
Signal Transduction
STAT3 Transcription Factor
Cell biology
Science
Primary Cell Culture
Adenocarcinoma
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Stomach Neoplasms
Cell Line
Tumor
Gastric mucosa
medicine
Animals
Humans
Gene silencing
Interleukin-6
Gene Expression Profiling
Epithelial Cells
General Chemistry
NFKB1
Mice
Inbred C57BL
030104 developmental biology
Gastric Mucosa
Tissue Array Analysis
Cancer cell
biology.protein
Cancer research
lcsh:Q
Carcinogenesis
Zdroj: Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019)
Nature Communications
ISSN: 2041-1723
Popis: 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.
Trefoil factor 1 (TFF1) is a protein secreted by the gastric mucosa that protects against gastric tumourigenesis. Here, the authors show that TFF1 inhibits the oncogenic inflammatory response and IL-6-mediated STAT3 activation by interfering with the binding of IL6 to its receptor IL6Rα.
Databáze: OpenAIRE
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