Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis

Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to co...

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Main Authors:	Soutto, Mohammed, Romero-Gallo, Judith, Krishna, Uma, Piazuelo, M. Blanca, Washington, M. Kay, Belkhiri, Abbes, Peek, Richard M., El-Rifai, Wael
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627225/

id	pubmed-4627225
recordtype	oai_dc
spelling	pubmed-46272252015-11-09 Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis Soutto, Mohammed Romero-Gallo, Judith Krishna, Uma Piazuelo, M. Blanca Washington, M. Kay Belkhiri, Abbes Peek, Richard M. El-Rifai, Wael Priority Research Paper Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to control (p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes (CCND1 and c-MYC), as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori-induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1-KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1-KO, as compared to Tff1-WT mice (p < 0.05). Only 10% of uninfected Tff1-KO mice, as opposed to one-third of H. pylori-infected Tff1-KO mice, developed invasive adenocarcinoma (p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori-mediated oncogenic activation of β-catenin and gastric tumorigenesis. Impact Journals LLC 2015-04-27 /pmc/articles/PMC4627225/ /pubmed/25980439 Text en Copyright: © 2015 Soutto et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Soutto, Mohammed Romero-Gallo, Judith Krishna, Uma Piazuelo, M. Blanca Washington, M. Kay Belkhiri, Abbes Peek, Richard M. El-Rifai, Wael
spellingShingle	Soutto, Mohammed Romero-Gallo, Judith Krishna, Uma Piazuelo, M. Blanca Washington, M. Kay Belkhiri, Abbes Peek, Richard M. El-Rifai, Wael Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
author_facet	Soutto, Mohammed Romero-Gallo, Judith Krishna, Uma Piazuelo, M. Blanca Washington, M. Kay Belkhiri, Abbes Peek, Richard M. El-Rifai, Wael
author_sort	Soutto, Mohammed
title	Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
title_short	Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
title_full	Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
title_fullStr	Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
title_full_unstemmed	Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
title_sort	loss of tff1 promotes helicobacter pylori-induced β-catenin activation and gastric tumorigenesis
description	Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to control (p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes (CCND1 and c-MYC), as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori-induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1-KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1-KO, as compared to Tff1-WT mice (p < 0.05). Only 10% of uninfected Tff1-KO mice, as opposed to one-third of H. pylori-infected Tff1-KO mice, developed invasive adenocarcinoma (p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori-mediated oncogenic activation of β-catenin and gastric tumorigenesis.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627225/
_version_	1613495289130254336

Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis

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