ABSTRACT
Helicobacter pylori encoded CagA is presently the only known virulence factor that is injected into gastric epithelial cells where it destroys apical junctional complexes and induces dedifferentiation of gastric epithelial cells, leading to H. pylori-related gastric carcinogensis. However, little is known about the molecular mechanisms by which CagA mediates these changes. Caudal-related homeobox 2 (Cdx2) is an intestine-specific transcription factor highly expressed in multistage tissues of dysplasia and cancer. One specific target of Cdx2, Claudin-2, is involved in the regulation of tight junction (TJ) permeability. In this study, our findings showed that the activity of Cdx2 binding to Cdx binding sites of CdxA (GTTTATG) and CdxB (TTTTAGG) of probes corresponding to claudin-2 flanking region increased in AGS cells, infected with CagA positive wild-type strain of H. pylori, compared to CagA negative isogenic mutant-type strain. Moreover, Cdx2 upregulated claudin-2 expression at transcriptional level and translational level. In the meantime, we found that TJs of AGS cells, infected with CagA positive wild-type strain of H. pylori, compared to CagA negative isogenic mutant-type strain, were more severely destroyed, leading to wider cell gap, interference of contact, scattering and highly elevated migration of cells. Herein, this study is firstly demonstrated that H. pylori-encoded CagA disrupts TJs and induces invasiveness of AGS gastric carcinoma cells via Cdx2-dependent targeting of Claudin-2. This provides a new mechanism whereby CagA induced dedifferentiation of AGS cells, leading to malignant behavior of biology.
Subject(s)
Adenocarcinoma/microbiology , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , Claudin-2/genetics , Helicobacter pylori/genetics , Homeodomain Proteins/genetics , Stomach Neoplasms/microbiology , Tight Junctions/microbiology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Antigens, Bacterial/metabolism , Bacterial Proteins/metabolism , Binding Sites , CDX2 Transcription Factor , Cell Dedifferentiation , Cell Line, Tumor , Claudin-2/metabolism , Epithelial Cells/metabolism , Epithelial Cells/microbiology , Epithelial Cells/pathology , Gene Expression Regulation , Helicobacter pylori/growth & development , Helicobacter pylori/pathogenicity , Homeodomain Proteins/metabolism , Host-Pathogen Interactions , Humans , Neoplasm Invasiveness , Protein Binding , Signal Transduction , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Tight Junctions/metabolism , Tight Junctions/pathologyABSTRACT
OBJECTIVE: To investigate the expression of syndecan-1 protein at different stages in the course of gastric carcinoma and its significance in carcinogenesis and metastasis. METHODS: There were 56 cases of chronic gastritis, 50 cases of chronic atrophic gastritis, 59 cases of intestinal metaplasia, 61 cases of displasia, and 112 cases of gastric carcinoma. Among the carcinoma cases, 55 were without and 57 with lymph node metastases. All paraffin-embedded tissue samples were assessed by immunohistochemistry. RESULTS: The syndecan-1 positive rate was 96.43% (54/56) in gastritis, 98.00% (49/50) in chronic atrophic gastritis, 100.00% (59/59) in intestinal metaplasia, 91.80% (56/61) in displasia, 45.45% (25/55) in gastric carcinoma without, and 24.56% (14/57) in gastric carcinoma with lymph node metastases. There was no significant difference among chronic gastritis, chronic atrophic gastritis and intestinal metaplasia (P > 0.05). There was a significant difference between displasia group and gastric carcinoma group (P <0.05), as well as between gastric carcinoma with and without lymph node metastases. There was a significant difference among well, moderately and poorly differentiated carcinoma groups. CONCLUSION: A decreasing expression of syedecan-1 in the development of gastric carcinoma is related with gastric carcinogenesis, and it may further promote metastasis of gastric carcinoma.
Subject(s)
Gastric Mucosa/chemistry , Precancerous Conditions/metabolism , Stomach Neoplasms/metabolism , Syndecan-1/biosynthesis , Adult , Aged , Female , Gastric Mucosa/pathology , Gastritis/metabolism , Gastritis/pathology , Humans , Immunohistochemistry , Lymphatic Metastasis , Male , Metaplasia , Middle Aged , Neoplasm Staging , Precancerous Conditions/pathology , Stomach/chemistry , Stomach/pathology , Stomach Neoplasms/pathologyABSTRACT
OBJECTIVE: To investigate the expression of microvessel density (MVD) in multistep tissue of gastric carcinoma and CD34 in the multistep tissue of gastric carcinogens. METHODS: 277 specimens of gastric diseases, 56 specimens of chronic gastritis, 50 specimens of chronic atrophic gastritis, 59 specimens of intestinal metaplasia, 61 specimens of dysplasia, 57 specimens of gastric carcinoma with lymph node metastases, and 55 specimens of gastric carcinoma without lymph node metastases, obtained from pathological department, Sun Yat-sen university, underwent pathological examination and immunohistochemistry to detect the expression of CD34 antigen that is expressed only in the endothelial cells in tumor. RESULTS: The mean MVD was 13 +/- 10 in the specimens of chronic gastritis, 11 +/- 7 in the chronic atrophic gastritis group, 13 +/- 9 in the intestinal metaplasia group, 17 +/- 10 in the dysplasia group, 27 +/- 11 in the gastric carcinoma without lymph node metastases group, and 28 +/- 10 in the gastric carcinoma with lymph node metastases group. There were not significant differences in MVD among the chronic gastritis group, chronic atrophic gastritis group, and intestinal metaplasia group (all P > 0.05), there was a significant difference in MVD between the chronic gastritis group and dysplasia group (P < 0.05). In the specimens of gastric carcinoma, there were no significant difference in MVD between those with and without lymph node metastases (P > 0.05), and between those of high and low differentiation degrees (both P < 0.05). CONCLUSION: The increase of expression of CD34 in the multistage tissues of gastric carcinoma is associated with the genesis of gastric cancer, and not be related to the gastric carcinoma metastases.