Epigenetic regulation of tumor suppressors by helicobacter pylori enhances ebv-induced proliferation of gastric epithelial cells
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Helicobacter pylori and Epstein-Barr virus (EBV) are two well-known contributors to cancer and can establish lifelong persistent infection in the host. This leads to chronic inflammation, which also contributes to development of cancer. Association with H. pylori increases the risk of gastric carcinoma, and coexistence with EBV enhances proliferation of infected cells. Further, H. pylori-EBV coinfection causes chronic inflammation in pediatric patients. We have established an H. pylori-EBV coinfection model system using human gastric epithelial cells. We showed that H. pylori infection can increase the oncogenic phenotype of EBV-infected cells and that the cytotoxin-associated gene (CagA) protein encoded by H. pylori stimulated EBV-mediated cell proliferation in this coinfection model system. This led to increased expression of DNA methyl transferases (DNMTs), which reprogrammed cellular transcriptional profiles, including those of tumor suppressor genes (TSGs), through hypermethylation. These findings provide new insights into a molecular mechanism whereby cooperativity between two oncogenic agents leads to enhanced oncogenic activity of gastric cancer cells.
IMPORTANCE We have studied the cooperativity between H. pylori and EBV, two known oncogenic agents. This led to an enhanced oncogenic phenotype in gastric epithelial cells. We now demonstrate that EBV-driven epigenetic modifications are enhanced in the presence of H. pylori, more specifically, in the presence of its CagA secretory antigen. This results in increased proliferation of the infected gastric cells. Our findings now elucidate a molecular mechanism whereby expression of cellular DNA methyl transferases is induced influencing infection by EBV. Hypermethylation of the regulatory genomic regions of tumor suppressor genes results in their silencing. This drastically affects the expression of cell cycle, apoptosis, and DNA repair genes, which dysregulates their associated processes, and promotion of the oncogenic phenotype.
Helicobacter pylori functions together with Epstein-Barr virus (EBV) as a group 1 carcinogen which contributes to the development of gastric cancer (GC) (1, 2). EBV is associated with several types of lymphoid and epithelial cancers, including GC (3–5). Previous studies also suggested that EBV can transform primary gastric epithelial cells in vitro (6). Therefore, EBV is likely not a passive carrier but an active oncogenic virus contributing to early events in development of GC (4, 7). More importantly, EBV-positive GC harbors EBV DNA in a uniform, monoclonal presence in all carcinoma cells (7, 8), and patients show high antibody titers against EBV prior to diagnosis (9). In a study with pediatric patients, coinfection with H. pylori and EBV caused severe gastritis and chronic inflammation compared to individual infection of the respective pathogens (10). Further, many reports have highlighted the significance of EBV and H. pylori in GC. However, not much has been done to investigate the molecular mechanism linked to coinfection of these agents or the degree or extent of associated pathologies, in this case, those represented by gastric cancer.
Pathogens coexisting with host cells can act as effectors of gene regulation through epigenetic modifications. This impacts the overall etiology and pathogenesis associated with the respective disease. For example, the periodontal bacterium Porphyromonas gingivalis can induce EBV reactivation through chromatin modification (11). This bacterium-virus synergy affects EBV-associated periodontal pathology (11). Furthermore, H. pylori and EBV have also been shown to impact epigenetic modifications of host cells (12, 13). This relationship, which exists within the microbial milieu and modulates host gene expression, can directly impact disease pathology.
introduction:
We investigated the molecular mechanism to elucidate the underlying strategy, which involves cooperation of H. pylori in EBV-driven proliferation of gastric epithelial cells. We developed an H. pylori and EBV coinfection model by the use of NCI-N87 human gastric epithelial cells, which is an excellent system mimicking human gastric epithelium (14). We demonstrated that the cytotoxin-associated gene (CagA) protein encoded by H. pylori promoted EBV-mediated proliferation of infected cells in our model system. Furthermore, we determined that the epigenetic status of EBV-infected cells was modulated as a consequence of H. pylori coinfection. This reprogramming resulted in upregulation of DNA methyl transferases (DNMTs), known epigenetic modifiers, leading to promoter methylation of CpG-rich islands of cell cycle-, DNA repair-, and apoptosis-related tumor suppressor genes (TSGs). Hypermethylation of the regulatory regions of these TSGs resulted in changes in cellular transcription profiles and the microenvironment that favored oncogenesis.