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Coexpression of Helicobacter Pylori’s Proteins CagA and HspB Induces Cell Proliferation in AGS Gastric Epithelial Cells, Independently from the Bacterial Infection¹

Department of Medicine and Public Health, Section of Clinical Anatomy [A. D. L.], Department of Biochemistry and Biophysics "F. Cedrangolo," Section of Anatomical Pathology [A. B.], and Department of General Pathology and Oncology, "Centro sperimentale S. Andrea delle Dame," [L. A.], Second University of Naples, 80138 Naples; Laboratory C, Department for the Development of Therapeutic Programs, Regina Elena Cancer Institute, 00158 Rome [A. B., P. R., M. G. P.]; Pathology and Clinical Laboratory [A. T.] and Division of Gastroenterology [N. G., L. P., V. D., S. I., G. I.], San G. Moscati Hospital, 83100 Avellino; and Digestive Endoscopy and Gastroenterology Division, San Martino Hospital, 16100 Genoa [M. C. P.], Italy

Adenocarcinoma of the stomach is the second most common cause of cancer mortality in the world. The purpose of this study was to evaluate the potential role in carcinogenesis of two secreted Helicobacter pylori’s proteins, CagA and HspB, both shown to increase the risk of gastric carcinoma in patients infected with H. pylori-positive strain. The effects of these two proteins on cell kinetics and the ability to selectively affect the expression of cell cycle-related proteins by transfection of a human gastric epithelial cell line (AGS) were analyzed. Using a genomic library of H. pylori, we isolated and cloned CagA and HspB. The effects of the overexpression of these proteins on cell growth were analyzed in AGS cells by immunoblots, proliferation assay, and flow cytometry. Coexpression of CagA and HspB in AGS cells in the first 48 h caused an increase of the level of E2F transcription factor, cyclin D3, and phosphorylated retinoblastoma protein, all involved in the G₁-S checkpoint of the cell cycle. Consistently, an increase of cell proliferation, corresponding to an augment of the fraction of the cells in the S-G₂-M phase of the cell cycle, was also demonstrated. Moreover, an increase of c-jun protein levels, but not of c-fos, was also found after coexpression of CagA and HspB. All these data suggest that CagA and HspB, independently from the bacterial infection, have a direct effect on the cell growth of the gastric cells acting on the G₁-S checkpoint of the cell cycle.