Helicobacter-induced Intestinal Metaplasia in the Stomach Correlates with Elk-1 and Serum Response Factor Induction of Villin

Juanita L. Merchant,Gabriele Rieder,Deborah L. Gumucio,Blair Madison,Xiaotan T. Qiao,Arthur J. Tessier

doi:10.1074/jbc.m413399200

Juanita L. Merchant, Gabriele Rieder + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m413399200

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Abstract

Chronic Helicobacter pylori infection results in serious sequelae, including atrophy, intestinal metaplasia, and gastric cancer. Intestinal metaplasia in the stomach is defined by the presence of intestine-like cells expressing enterocyte-specific markers, such as villin. In this study, we demonstrate that villin is expressed in intestine-like cells that develop after chronic infection with H. pylori in both human stomach and in a mouse model. Transfection studies were used to identify specific regions of the villin promoter that are inducible by exposure of the cells to H. pylori. We demonstrated that induction of the villin promoter by H. pylori in a human gastric adenocarcinoma cell line (AGS) required activation of the Erk pathway. Elk-1 and the serum response factor (SRF) are downstream transcriptional targets of the Erk pathway. We observed inducible binding of Elk-1 and the SRF after 3 and 24 h of treatment with H. pylori, suggesting that the bacteria alone are sufficient to initiate a cascade of signaling events responsible for villin expression. Thus, H. pylori induction of villin in the stomach correlates with activation and cooperative binding of Elk-1 and the SRF to the proximal promoter of villin.

Highlights

Chronic inflammation of the gastric mucosa develops in response to Helicobacter pylori infection or bacterial overgrowth in the hypochlorhydric stomach [1, 2]
We demonstrate that villin is expressed in intestine-like cells that develop after chronic infection with H. pylori in both human stomach and in a mouse model
We showed that the first 554 bp of the villin promoter contain elements capable of responding to H. pylori in culture. Within this proximal promoter region, we found that a serum response element (SRE)1 confers inducible regulation of the villin promoter by H. pylori and that Elk-1 and the serum response factor (SRF) form a ternary complex at this element

Summary

Introduction

Chronic inflammation of the gastric mucosa (chronic gastritis) develops in response to Helicobacter pylori infection or bacterial overgrowth in the hypochlorhydric stomach [1, 2]. Proliferation of mucous cell types with evidence of an intestinal phenotype (intestinal metaplasia) is a major precursor lesion in gastric cancer [3]. The gastric epithelium develops from intestinal endoderm by 16 days post-. Fetal intestinal markers cease to be expressed in the gastric epithelium. Re-expression of intestine-specific genes in the adult stomach represents a shift to a metaplastic phenotype that correlates with increased gastric proliferation. Microvilli develop but do not respond normally to calcium-dependent signals, implicating the protein in the response to cell injury [17, 18]. Villin is an important marker of the pre-neoplastic cell type that forms in the gut in response to chronic injury [20]. Within this proximal promoter region, we found that a serum response element (SRE) confers inducible regulation of the villin promoter by H. pylori and that Elk-1 and the serum response factor (SRF) form a ternary complex at this element

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