乙型肝炎病毒大表面蛋白通过诱导胞质分裂失败而引发肝细

StephenW

J Pathol. 2018 Sep 23. doi: 10.1002/path.5169. [Epub ahead of print]
Hepatitis B virus large surface protein is priming for hepatocellular carcinoma development via induction of cytokinesis failure.
Musa J1, Li J1, Grünewald TGP1,2,3,4.
Author information

1
    Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
2
    Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
3
    German Cancer Consortium (DKTK), Munich, Germany.
4
    German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

Chronic hepatitis B virus (HBV) infection is a main risk factor for development of liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV vaccination and antiviral therapy lead to substantial risk reduction for HCC development, it is evident that both can reduce, but not completely eliminate the risk. High serum levels of HBV surface antigen (HBsAg) were shown to predict disease progression of chronic HBV infection in patients harboring low viral load, and in line with this, HBV surface proteins were shown to exert oncogenic functions. As HBsAg seroclearance is infrequently achieved in patients who have undergone antiviral therapy, it is necessary to gain further insights into molecular mechanisms of HBsAg seroclearance failure after antiviral therapy and HCC development mediated by HBV surface proteins. A recent study published in this journal has shown that the HBsAg large surface protein (LHBs) contributes to HCC development by inducing cytokinesis failure and consequent aneuploidy via induction of DNA damage and polo-like kinase 1 (PLK1)-mediated G2/M checkpoint failure in hepatocytes. Inhibition of PLK1 by a PLK1-specific small molecule inhibitor was shown to restore G2/M checkpoint in vitro and to reduce tumor burden in vivo. The initial LHBs-induced hepatocyte aneuploidy may give rise to further aneuploidy and thereby lead to self-propagating cycles of chromosomal instability driving intra-tumor heterogeneity and clonal cancer evolution. Thus, LHBs-induced cytokinesis failure may be a priming event for HCC development. In conclusion, the study not only provides further mechanistic insights into the oncogenic role of LHBs, but also identifies a potential target to interfere with the circle of LHBs-induced aneuploidy, which may be especially useful in patients showing failure of HBsAg seroclearance after antiviral therapy. This article is protected by copyright. All rights reserved.
KEYWORDS:

aneuploidy; cytokinesis; hepatitis B virus; hepatocellular carcinoma; polo-like kinase 1

PMID:
    30246253
DOI:
    10.1002/path.5169

StephenW

J Pathol。 2018年9月23日doi：10.1002 / path.5169。 [提前打印]
乙型肝炎病毒大表面蛋白通过诱导胞质分裂失败而引发肝细胞癌的发展。
Musa J1，Li J1，GrünewaldTGP1,2,3,4。
作者信息

1
    德国慕尼黑LMU慕尼黑大学医学院病理学研究所儿科肉瘤生物学Max-Eder研究小组。
2
    德国慕尼黑慕尼黑大学医学院病理学研究所。
3
    德国癌症联合会（DKTK），德国慕尼黑。
4
    德国癌症研究中心（DKFZ），德国海德堡。

抽象

慢性乙型肝炎病毒（HBV）感染是肝硬化和肝细胞癌（HCC）发展的主要危险因素。虽然HBV疫苗接种和抗病毒治疗可以显着降低HCC发展的风险，但很明显，两者都可以减少但不能完全消除风险。显示高血清水平的HBV表面抗原（HBsAg）预测具有低病毒载量的患者中慢性HBV感染的疾病进展，并且与此一致，HBV表面蛋白显示出发挥致癌功能。由于接受抗病毒治疗的患者很少发生HBsAg血清清除，因此有必要进一步了解抗病毒治疗后HBsAg血清清除失败和HBV表面蛋白介导的HCC发展的分子机制。该杂志最近发表的一项研究表明，HBsAg大表面蛋白（LHBs）通过诱导DNA损伤和polo样激酶1（PLK1）介导的G2 / M检查点失败诱导胞质分裂失败和随后的非整倍性，从而促进HCC的发展。在肝细胞中。 PLK1特异性小分子抑制剂对PLK1的抑制显示在体外恢复G2 / M检查点并减少体内肿瘤负荷。最初的LHB诱导的肝细胞非整倍性可能引起进一步的非整倍性，从而导致染色体不稳定的自我繁殖循环，从而驱动肿瘤内异质性和克隆性癌症进化。因此，LHB诱导的胞质分裂失败可能是HCC发展的启动事件。总之，该研究不仅为LHBs的致癌作用提供了进一步的机制见解，而且还确定了干扰LHBs诱导的非整倍性循环的潜在目标，这对于抗病毒治疗后HBsAg血清清除失败的患者尤其有用。 。本文受版权保护。版权所有。
关键词：

非整倍体;胞质分裂;乙型肝炎病毒;肝细胞癌; polo样激酶1

结论：
    30246253
DOI：
    10.1002 / path.5169