华人学者发现乙肝病毒感染诱发肝癌的机制！

乌龟发表于 2018-10-5 17:16:58

华人学者发现乙肝病毒感染诱发肝癌的机制！

乙肝病毒感染是世界范围一个严重的社会健康问题，长期感染的个人有发展为肝硬化和肝癌更高的风险。因缺乏方便且有效的体外病毒感染模型，乙肝病毒引发肝癌的分子机制还不清楚。

通过研发乙肝病毒高效体外感染人原代肝细胞模型，研究人员研究了乙肝病毒怎样扰乱感染的肝细胞的基因表达和信号通路，及这些效果是否与乙肝病毒感染及乙肝病毒相关的肝癌有关。通过使用一个人类生长因子抗体阵列，研究人员首先揭示了乙肝病毒感染导致人原代肝细胞产生的生长因子的一个不同的侧面，由上清中蛋白质的转化因子β家族(TGF-β)的更低水平来标示。转录组分析显示了在乙肝病毒感染时，细胞增殖和细胞周期控制通路的多种变化。一个人类细胞周期阵列验证了与感染乙肝病毒的人原代肝细胞的细胞周期有关的多于20个基因的反常有关。细胞周期分析证明乙肝病毒感染的人原代肝细胞在G2/M 期增多，而培养的人原代肝细胞主要在G0/G1 期增多。乙肝病毒前病毒的宿主因素，如PPARA, RXRA和CEBPB在乙肝病毒感染时上调，尤其在G2/M 期在细胞中增多。总之，这些结果支持了乙肝病毒下调了细胞周期控制来制造一个适宜乙肝病毒感染的细胞环境。通过扰乱感染细胞的细胞周期调节，乙肝病毒能巧合地引发一个癌变前的表型，它使感染的肝细胞倾向于随后的恶性转化。实验结果在乙肝病毒感染的大猩猩上得到了验证。

本研究奠定了乙肝病毒感染诱发肝癌的理论基础，也为慢性乙型肝炎及肝癌的治疗提供了重要的参考依据。

图1人类生长因子阵列

第一作者

夏宇尘，现为武汉大学基础医学院教授，博导，病毒学国家重点实验室PI，国家“千人计划”青年项目入选者。主要研究成果在Science, Gastroenterology, Journal of Hepatology, Journal of Virology等学术期刊以第一作者发表，其中两篇一作文章入选ESI高被引论文。现为国际肝癌协会会员、欧洲肝病协会会员。担任Gastroenterology, Hepatology, eLIFE, Journal of Virology，Antiviral Research等杂志审稿人。

通讯作者

连展扬（T. Jake Liang），M.D，美国医学院院士，现任美国国立卫生研究院NIDDK转化研究副主任，肝病教研室主任。哈佛大学本科毕业后，进入哈佛医学院获得医学博士学位。连展扬是国际知名的病毒性肝炎和肝脏疾病领域的领导者，有300多篇科学论文发表在高影响力的期刊上，包括NEJM，Science，Nature，Nature Medicine， Science Trans Med，Nature Genetics，Ann Med of Int Med，J Clin Invest等，并参与编写多本学术著作。连展扬曾担任Gastroenterology副主编（IF 20）（1996-2001,2016-2021），Hepatology（IF 14）（2001-2006）和 Gut（IF 18）（2014-2017）。他1996当选为美国临床医学研究会会士，2002年当选美国医师协会会士和 2016年当选美国国家医学院院士，2017年当选美国科学促进会（AAAS）会士。他在许多学术界都很活跃专业协会，包括ASCI，美国肝脏研究协会（AASLD）和美国胃肠病学协会（AGA）。曾担任AASLD主席。

ABSTRACT
Hepatitis B virus (HBV) infection is a major health problem worldwide, and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. Using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and signaling pathways of infected hepatocytes and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of the transforming growth factor β (TGF-β) family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 genes associated with the cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase compared to the predominantly G0/G1 phase of cultured PHHs. HBV proviral host factors, such as PPARA, RXRA, and CEBPB, were upregulated upon HBV infection and particularly enriched in cells in the G2/M phase. Together, these results support the notion that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive HBV infection. By perturbing cell cycle regulation of infected cells, HBV may coincidently induce a premalignant phenotype that predisposes infected hepatocytes to subsequent malignant transformation.

IMPORTANCE
Hepatitis B virus (HBV) infection is a major health problem with high risk of developing hepatocellular carcinoma (HCC). By using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expression and whether these effects are relevant to HBV-associated HCC. HBV induced a distinct profile of growth factor production, marked particularly by significantly lower levels of the transforming growth factor β(TGF-β) family of proteins. Transcriptome profiling revealed multiple changes in cell proliferation and cell cycle control pathways. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase. HBV proviral host factors were upregulated upon infection and particularly enriched in cells in the G2/M phase. Together, these results support the notion that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive infection. This may coincidently induce a
premalignant phenotype that predisposes infected hepatocytes to subsequent malignant transformation.

DOI: 10.1128/JVI.00722-18

乌龟发表于 2018-10-5 17:22:09