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

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.Chronic inflammation of the gastric mucosa (chronic gastritis) develops in response to Helicobacter pylori infection or bacterial overgrowth in the hypochlorhydric stomach (1, 2). Over time, the inflammatory process progresses, and alteration of the epithelial cell population occurs, which includes gradual loss of parietal cells coinciding with an increase in the number of mucous cells. Proliferation of mucous cell types with evidence of an intestinal phenotype (intestinal metaplasia) is a major precursor lesion in gastric cancer (3). Moreover, intestinal metaplasia is a lesion that develops in a variety of cancers derived from organs of the forestomach (4 -6). Interestingly, intestinal metaplasia in different organs all express protein markers commonly found in normal intestinal enterocytes, e.g. TFF3, Cdx2, villin (7-10). The gastric epithelium develops from intestinal endoderm by 16 days postcoitum when the pyloric border is formed. At that time, 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.Villin is expressed in primitive endoderm by embryonic day 5 and coalesces at the apical surface by day 8.5 postcoitum as the microvilli of the gut are being formed (11-13). By 16 days postcoitum, there is a one-cell distinction between villin expression in the duodenum and minimal expression in the antral glands (14). By postnatal day 1, villin expression in the stomach has completely receded. Thus, there is a complete absence of villin expression in the corpus of the mouse stomach (15). Villin is a structural protein regulated by increased intracellular calcium that in turn binds to actin and contributes to the formation of micr...

Interaction of Phospholipase C-γ1with Villin Regulates Epithelial Cell Migration

“…Villin is also expressed in other adenocarcinomas even though it is absent from normal tissue such as in Barrett's metaplasia and gastric cardia adenocarcinomas. More recently, chronic Helicobacter pylori infection has been shown to induce endogenous villin expression in the stomach (11). Consistent with this and other studies, it has been suggested that villin expression arises in these tissues in response to chronic injury and may be a marker of pre-neoplastic lesions and may even participate in the altered genetic program that results in intestinal metaplasia (12).…”

Frequent Loss of Brm Expression in Gastric Cancer Correlates with Histologic Features and Differentiation State

“…This cytoskeletal protein is also known to be a calcium-regulated actinbinding protein and to display strict tissue-specific expression (38). Villin is never expressed in the normal gastric mucosa, but is frequently induced in the gastric mucosa in connection with intestinal metaplastic change, a well characterized precancerous condition of the stomach (39). Consequently, villin is often ectopically expressed in stomach malignancies, particularly in gastric adenocarcinoma (38,40).…”

Helicobacter pylori and gastric cancer

“…Transgenic mice expressing the homeobox gene Cdx1 in gastric mucosa develop intestinal metaplasia in a similar, but not identical, fashion to the Cdx2 overexpressing transgenic mice previously described [41]. H. pylori has also been shown to induce the villin promoter in gastric adenocarcinoma (AGS) epithelial cells via activation and cooperative binding of Elk-1 and serum response factor (SRF) [42]. H. pylori infection of gastric epithelial cell lines in vitro and Mongolian gerbils has also been shown to be associated with decreased expression of inhibitors of DNA binding transcription factors [43].…”