華人學者發現乙肝病毒感染誘發肝癌的機制！

乙肝病毒感染是世界範圍一個嚴重的社會健康問題，長期感染的個人有發展為肝硬化和肝癌更高的風險。因缺乏方便且有效的體外病毒感染模型，乙肝病毒引發肝癌的分子機制還不清楚。

通過研發乙肝病毒高效體外感染人原代肝細胞模型，研究人員研究了乙肝病毒怎樣擾亂感染的肝細胞的基因表達和信號通路，及這些效果是否與乙肝病毒感染及乙肝病毒相關的肝癌有關。通過使用一個人類生長因子抗體陣列，研究人員首先揭示了乙肝病毒感染導致人原代肝細胞產生的生長因子的一個不同的側面，由上清中蛋白質的轉化因子β家族(TGF-β)的更低水平來標示。轉錄組分析顯示了在乙肝病毒感染時，細胞增殖和細胞周期控制通路的多種變化。一個人類細胞周期陣列驗證了與感染乙肝病毒的人原代肝細胞的細胞周期有關的多於20個基因的反常有關。細胞周期分析證明乙肝病毒感染的人原代肝細胞在G2/M 期增多，而培養的人原代肝細胞主要在G0/G1 期增多。乙肝病毒前病毒的宿主因素，如PPARA, RXRA和CEBPB在乙肝病毒感染時上調，尤其在G2/M 期在細胞中增多。總之，這些結果支持了乙肝病毒下調了細胞周期控制來製造一個適宜乙肝病毒感染的細胞環境。通過擾亂感染細胞的細胞周期調節，乙肝病毒能巧合地引發一個癌變前的表型，它使感染的肝細胞傾向於隨後的惡性轉化。實驗結果在乙肝病毒感染的大猩猩上得到了驗證。

本研究奠定了乙肝病毒感染誘發肝癌的理論基礎，也為慢性乙型肝炎及肝癌的治療提供了重要的參考依據。

圖1 人類生長因子陣列

第一作者

夏宇塵，現為武漢大學基礎醫學院教授，博導，病毒學國家重點實驗室PI，國家「千人計劃」青年項目入選者。主要研究成果在Science,Gastroenterology, Journal of Hepatology, Journal of Virology等學術期刊以第一作者發表，其中兩篇一作文章入選ESI高被引論文。現為國際肝癌協會會員、歐洲肝病協會會員。 擔任Gastroenterology, Hepatology, eLIFE, Journal of Virology，Antiviral Research等雜誌審稿人。

通訊作者

連展揚（T. Jake Liang），M.D，美國醫學院院士，現任美國國立衛生研究院NIDDK轉化研究副主任，肝病教研室主任。哈佛大學本科畢業後，進入哈佛醫學院獲得醫學博士學位。連展揚是國際知名的病毒性肝炎和肝臟疾病領域的領導者，有300多篇科學論文發表在高影響力的期刊上，包括NEJM，Science，Nature，Nature Medicine， Science Trans Med，Nature Genetics，Ann Med of Int Med，J Clin Invest等，並參與編寫多本學術著作。連展揚曾擔任Gastroenterology副主編（IF 20）（1996-2001,2016-2021），Hepatology（IF 14）（2001-2006）和 Gut（IF 18）（2014-2017）。他1996當選為美國臨床醫學研究會會士，2002年當選美國醫師協會會士和 2016年當選美國國家醫學院院士，2017年當選美國科學促進會（AAAS）會士。他在許多學術界都很活躍 專業協會，包括ASCI，美國肝臟研究協會（AASLD）和美國胃腸病學協會（AGA）。曾擔任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 factorβ(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 G/G1phase 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 factorβ(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

本期編輯：烏龜，夏宇塵

喜歡這篇文章嗎？立刻分享出去讓更多人知道吧！