乙型肝炎病毒解除细胞周期，促进病毒复制和癌症前表型

StephenW

Hepatitis B Virus Deregulates the Cell Cycle To Promote Viral Replication and a Premalignant Phenotype
Yuchen Xia, Xiaoming Cheng, Yao Li, Kristin Valdez, Weiping Chen, T. Jake Liang
J.-H. James Ou, Editor
DOI: 10.1128/JVI.00722-18

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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.

StephenW

乙型肝炎病毒解除细胞周期，促进病毒复制和癌症前表型
夏雨辰，程晓明，姚莉，Kristin Valdez，陈卫平，T。Jake Liang
J.-H. James Ou，编辑
DOI：10.1128 / JVI.00722-18

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抽象

乙型肝炎病毒（HBV）感染是世界范围内的主要健康问题，并且慢性感染的个体具有发展为肝硬化和肝细胞癌（HCC）的高风险。 HBV引起HCC的分子机制在很大程度上是未知的。使用生物学相关的原发性人肝细胞（PHH）HBV感染系统，我们研究了HBV如何扰乱感染肝细胞的基因表达和信号传导途径，以及这些影响是否与生产性HBV感染和HBV相关的HCC相关。使用人生长因子抗体阵列，我们首先表明HBV感染诱导了PHH生长因子产生的明显特征，特别是上清液中转化生长因子β（TGF-β）蛋白家族水平显着降低。转录组分析接下来揭示了响应HBV感染的细胞增殖和细胞周期控制途径的多种变化。人细胞周期PCR阵列验证了与HBV感染的PHH中的细胞周期相关的超过20种基因的失调。细胞周期分析表明，与培养的PHH的主要为G0 / G1期相比，HBV感染的PHH富含G2 / M期。 HBV前病毒因子如PPARA，RXRA和CEBPB在HBV感染时上调，特别是在G2 / M期细胞中富集。总之，这些结果支持HBV解除对细胞周期控制的控制以产生有利于HBV感染的细胞环境的观点。通过扰乱受感染细胞的细胞周期调节，HBV可以巧合地诱导预先恶化的表型，其使感染的肝细胞易于发生随后的恶性转化。

重要性乙型肝炎病毒（HBV）感染是一种主要的健康问题，具有发展为肝细胞癌（HCC）的高风险。通过使用生物学相关的原发性人肝细胞（PHH）HBV感染系统，我们研究了HBV如何扰乱基因表达以及这些效应是否与HBV相关的HCC相关。 HBV诱导了生长因子产生的明显特征，特别是由转化生长因子β（TGF-β）蛋白家族的水平显着降低。转录组分析揭示了细胞增殖和细胞周期控制途径的多种变化。细胞周期分析表明HBV感染的PHH富含G2 / M期。 HBV前病毒宿主因子在感染后上调，特别是在G2 / M期细胞中富集。总之，这些结果支持HBV解除对细胞周期控制的控制以产生有利于生产性感染的细胞环境的观点。这可能同时诱导预先恶化的表型，其使感染的肝细胞易于发生随后的恶性转化。