Objective: To determine the expression of E-cadherin, β-catenin, and transcription factor 4 (TCF4) proteins in gastric diseases with relation to Helicobacter pylori infection. Methods: A total of 309 patients including 60 with superficial gastritis (SG), 57 with atrophic gastritis (AG) and 192 with gastric cancer (GC), were enrolled. The expression of E-cadherin, β-catenin, TCF4 proteins in the gastric mucosa was detected by immunohistochemistry and H. pylori infection by immunohistochemistry and PCR. Results: The expression rates of E-cadherin were significantly higher in SG and AG than in GC (P<0.01), while those of β-catenin in the nucleus were significantly lower in SG and AG than in GC (P<0.05). In GC cases, the expression rates of E-cadherin, β-catenin and TCF4 were significantly higher in the intestinal type than in the diffuse type (P<0.05). In GC patients, the expression rate of E-cadherin was significantly higher in the presence of H. pylori than in the absence of infection (P=0.011). Moreover, the expression level of TCF4 and β-catenin protein was significantly higher in the nucleus and cytoplasm in H. pylori positive than in H. pylori negative GC patients, especially in those with the intestinal type (all P < 0.05). Conclusion: The expression of E-cadherin and β-catenin progressively decreases during the process of GC tumorigenesis, while overexpression of TCF4 occurs. H. pylori infection is associated with a significant increase in the expression of E-cadherin and β-catenin in the cytoplasm and nucleus in GC patients, especially those with the intestinal type.
Epidemiologic studies have demonstrated that Helicobacter pylori infection is associated with increased risk for the development of gastric cancer. Animal studies have also shown that H. pylori infection leads to gastric carcinogenesis, especially intestinal phenotypes. However, no in vitro study has been carried out for cell transformation induced by H. pylori. The present study aimed to investigate whether 'chronic'H. pylori infection induces gastric epithelial cell transformation, and elucidate the underlying mechanisms of transformation induced by H. pylori. The immortalized 'normal' gastric epithelial cell line, GES-1, was co-cultured for 45 days with H. pylori strains B975 and L301. The cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Ki-67 antigen, and colony formation assay. The cell transformation was determined by observing cell morphology and measuring the expression of E-cadherin, β-catenin, and transcription factor-4 (TCF-4) at both protein and mRNA levels. H. pylori induced morphologic changes in GES-1 cells and significantly increased the proliferation of GES-1 cells. Moreover, H. pylori up-regulated the expression of β-catenin and TCF-4, and also induced the nuclear accumulation of β-catenin. In addition, the diffusive gastric cancer-related gene, E-cadherin, was up-regulated at the protein level, but down-regulated at the mRNA level. H. pylori infection is capable of inducing GES-1 transformation to present with the characteristics of intestinal-type gastric cancers in vitro, likely through the β-catenin/TCF-4 signaling pathway.
Helicobacter pylori infection is the most important risk factor for gastric intestinal metaplasia (IM). Our previous study demonstrated that infection with H. pylori HpslyD-positive strains associated with IM. To further investigate the signalling pathway involved in HpSlyD-induced IM, CDX2 and VIL1 expressions were determined before and after HpSlyD application. TCTP was knocked down by siRNA or overexpressed by plasmid transfection. An HpSlyD binding protein was used to block HpSlyD’s enzymatic activity. The expression of CDX2 and TCTP in gastric diseases was measured by immunohistochemistry. Our results showed HpSlyD induced CDX2 and VIL1 expressions. TCTP protein expression was markedly increased after application of HpSlyD and in an HpSlyD-expressing stable cell line. Downregulation of TCTP protein led to decreased HpSlyD-induced CDX2 and VIL1. Overexpression of TCTP protein improved the expression of CDX2 and VIL1. Co-application of HpSlyD and FK506 led to significant reductions in CDX2, VIL1, and TCTP expression. Immunohistochemistry demonstrated that CDX2 and TCTP expression was higher in HpslyD-positive specimens compared with HpslyD-negative ones. Expression of CDX2 was positively correlated with TCTP in HpslyD-positive cells. Our study is the first to show that HpSlyD induction of CDX2 and VIL1 expression mediated through TCTP may contribute to IM in the stomach.
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