Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
mBio. 2018 Apr 24;9(2):e00649-18. doi: 10.1128/mBio.00649-18.
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 increases the risk of gastric carcinoma, and coexistence with EBV enhances proliferation of infected cells. Further, -EBV coinfection causes chronic inflammation in pediatric patients. We have established an -EBV coinfection model system using human gastric epithelial cells. We showed that infection can increase the oncogenic phenotype of EBV-infected cells and that the cytotoxin-associated gene (CagA) protein encoded by 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. We have studied the cooperativity between 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 , 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.
和 Epstein-Barr 病毒（EBV）是两种众所周知的癌症促进因子，能够在宿主中建立终身持续性感染。这导致慢性炎症，也有助于癌症的发展。与 相关联会增加胃癌的风险，并且与 EBV 的共存会增强受感染细胞的增殖。此外，-EBV 合并感染会导致儿科患者发生慢性炎症。我们使用人胃上皮细胞建立了一个 -EBV 合并感染模型系统。我们表明，感染可以增加 EBV 感染细胞的致癌表型，并且由 编码的细胞毒素相关基因（CagA）蛋白在这个合并感染模型系统中刺激 EBV 介导的细胞增殖。这导致 DNA 甲基转移酶（DNMTs）的表达增加，通过超甲基化重新编程细胞转录谱，包括肿瘤抑制基因（TSGs）。这些发现为两种致癌剂之间的协同作用导致胃癌细胞致癌活性增强的分子机制提供了新的见解。我们研究了两种已知致癌剂 和 EBV 之间的协同作用。这导致胃上皮细胞中增强的致癌表型。我们现在证明，在 的存在下，更具体地说，在其 CagA 分泌抗原的存在下，EBV 驱动的表观遗传修饰得到增强。这导致受感染的胃细胞增殖增加。我们的研究结果现在阐明了一个分子机制，其中细胞 DNA 甲基转移酶的表达被诱导，影响 EBV 的感染。肿瘤抑制基因的调节基因组区域的过度甲基化导致其沉默。这极大地影响了细胞周期、凋亡和 DNA 修复基因的表达，从而使它们相关的过程失调，并促进致癌表型。
