Yoon Hyunyoung, Jang Kyung Lib
Department of Microbiology, College of Natural Science, Pusan National University, Busan, 46241, Republic of Korea.
Heliyon. 2022 Jul 5;8(7):e09881. doi: 10.1016/j.heliyon.2022.e09881. eCollection 2022 Jul.
Dual infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) is closely associated with an increased risk of hepatocellular carcinoma; however, the underlying mechanism is poorly understood. In the present study, we found that HBV X protein (HBx) and HCV core protein work together to inhibit E-cadherin expression in human hepatoma cells. For this effect, they additively increased both the level and activity of enzymes, DNA methyltransferase 1, 3a, and 3b to induce promoter hypermethylation of E-cadherin in a p53-dependent fashion. Their additive effect on E-cadherin levels was reproduced in an HBV/HCV dual infection system using Huh7D-NTCP cells. As a result, HBV and HCV additively upregulated mesenchymal marker such as N-cadherin, Snail, Twist and Vimentin but cooperatively downregulated epithelial markers such as E-cadherin, Slug and Plakoglobin. In addition, the coinfected cells exhibited faster cell migration and higher invasion ability, as compared with monoinfection, which are hallmarks of epithelial-mesenchymal transition required for the initiation of metastasis in cancer progression.
乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）双重感染与肝细胞癌风险增加密切相关；然而，其潜在机制尚不清楚。在本研究中，我们发现HBV X蛋白（HBx）和HCV核心蛋白共同作用抑制人肝癌细胞中E-钙黏蛋白的表达。为此，它们以p53依赖的方式累加增加了DNA甲基转移酶1、3a和3b的水平及活性，从而诱导E-钙黏蛋白启动子高甲基化。它们对E-钙黏蛋白水平的累加效应在使用Huh7D-NTCP细胞的HBV/HCV双重感染系统中得到重现。结果，HBV和HCV累加上调间充质标志物，如N-钙黏蛋白、Snail、Twist和波形蛋白，但协同下调上皮标志物，如E-钙黏蛋白、Slug和桥粒斑珠蛋白。此外，与单一感染相比，双重感染的细胞表现出更快的细胞迁移和更高的侵袭能力，这是癌症进展中转移起始所需的上皮-间质转化的标志。
