乙型肝炎病毒X蛋白通过破坏肝脏多倍化促进DNA损伤的传播并

StephenW

Oncogene. 2018 Dec 11. doi: 10.1038/s41388-018-0607-3. [Epub ahead of print]
Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation.
Ahodantin J1,2,3, Bou-Nader M4,5,6, Cordier C7,8, Mégret J7,8, Soussan P1,2,3, Desdouets C4,5,6, Kremsdorf D9,10,11.
Author information

1
    Inserm U1135 CIMI-Paris, Team «Persistent Viral Infections», Paris, France.
2
    Université Pierre et Marie Curie, Paris, France.
3
    CNRS, ERL 8255, Paris, France.
4
    Inserm, U1016, Institut Cochin, Paris, France.
5
    CNRS, UMR8104, Paris, France.
6
    Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
7
    Cytometry Core Facility, Inserm US24/CNRS UMS 3633-SFR Necker, Paris, France.
8
    Faculté de Médecine, Paris Descartes, Paris, France.
9
    Inserm U1135 CIMI-Paris, Team «Persistent Viral Infections», Paris, France. [email protected].
10
    Université Pierre et Marie Curie, Paris, France. [email protected].
11
    CNRS, ERL 8255, Paris, France. [email protected].

Abstract

Hepatitis B virus X protein (HBx) contributes to Hepatitis B virus (HBV)-related liver cancer. However, its impact on hepatocyte proliferation and genomic stability remains elusive. We studied the role of HBx expression on the progression of cell cycle and liver polyploidization during proliferation and liver carcinogenesis. Full-length HBx transgenic mice (FL-HBx) were developed to investigate liver ploidy as well as hepatocyte proliferation, along normal liver maturation and during cancer initiation (chemical carcinogen treatment). Investigation of postnatal liver development in FL-HBx showed an aberrant G1/S and G2/M transitions, triggered (1) a delay of the formation of hepatocytes binucleation, (2) the early synthesis of polyploidy nuclei (≥4n) and (3) DNA damage appearance. Moreover, HBV infection during hepatocytes proliferation in a humanized liver mouse model led, to modifications in polyploidy of hepatocytes. In initiation of hepatocellular carcinoma, FL-HBx protein decreased ChK1 phosphorylation, Mre11 and Rad51 expression, upregulated IL-6 expression and impaired apoptosis. This was related to DNA damage accumulation in FL-HBx mice. At day 75 after initiation of hepatocellular carcinoma, FL-HBx mice revealed significant cell cycle changes related to the increased amount of 4n nuclei and of markers of cancer progenitor cells. Finally, PLK1 upregulation and p38/ERK activation in FL-HBx mice were implicated in aberrant polyploidization favoring DNA damage propagation and hepatocyte transformation. In conclusion, our data indicate that FL-HBx protein increases DNA damage through the hijack of hepatocyte polyploidization. That leads to enhancement of hepatocellular carcinoma initiation in an inflammatory context.

PMID:
    30538294
DOI:
    10.1038/s41388-018-0607-3

StephenW

癌基因。 2018年12月11日doi：10.1038 / s41388-018-0607-3。 [提前打印]
乙型肝炎病毒X蛋白通过破坏肝脏多倍化促进DNA损伤的传播并增强肝细胞癌的发生。
Ahodantin J1,2,3，Bou-Nader M4,5,6，Cordier C7,8，MégretJ7,8，Soussan P1,2,3，Desdouets C4,5,6，Kremsdorf D9,10,11。
作者信息

1
    Inserm U1135 CIMI-Paris，团队«持续性病毒感染»，法国巴黎。
2
    皮埃尔和玛丽居里大学，法国巴黎。
3
    CNRS，ERL 8255，巴黎，法国。
4
    Inserm，U1016，Institut Cochin，巴黎，法国。
五
    CNRS，UMR8104，巴黎，法国。
6
    UniversitéParisDescartes，SorbonneParisCité，巴黎，法国。
7
    Cytometry Core Facility，Inserm US24 / CNRS UMS 3633-SFR Necker，Paris，France。
8
    FacultédeMédecine，巴黎笛卡尔，巴黎，法国。
9
    Inserm U1135 CIMI-Paris，团队«持续性病毒感染»，法国巴黎。 [email protected]。
10
    皮埃尔和玛丽居里大学，法国巴黎。 [email protected]。
11
    CNRS，ERL 8255，巴黎，法国。 [email protected]。

抽象

乙型肝炎病毒X蛋白（HBx）有助于乙型肝炎病毒（HBV）相关的肝癌。然而，它对肝细胞增殖和基因组稳定性的影响仍然难以捉摸。我们研究了HBx表达在增殖和肝癌发生过程中细胞周期和肝脏多倍化进程中的作用。开发了全长HBx转基因小鼠（FL-HBx）以研究肝脏倍性以及肝细胞增殖，正常肝脏成熟和癌症发生期间（化学致癌物处理）。对FL-HBx出生后肝脏发育的研究显示，G1 / S和G2 / M转换异常，引发（1）肝细胞双核形成的延迟，（2）多倍体核的早期合成（≥4n）和（3） ）DNA损伤外观。此外，人源化肝小鼠模型中肝细胞增殖期间的HBV感染导致肝细胞多倍性的修饰。在肝细胞癌的起始过程中，FL-HBx蛋白降低ChK1磷酸化，Mre11和Rad51表达，上调IL-6表达并破坏细胞凋亡。这与FL-HBx小鼠中的DNA损伤积累有关。在肝细胞癌开始后第75天，FL-HBx小鼠显示出与4n细胞核和癌祖细胞标记物的增加量相关的显着细胞周期变化。最后，FL-HBx小鼠中的PLK1上调和p38 / ERK活化涉及有利于DNA损伤繁殖和肝细胞转化的异常多倍化。总之，我们的数据表明FL-HBx蛋白通过劫持肝细胞多倍化来增加DNA损伤。这导致在炎症环境中肝细胞癌起始的增强。

结论：
    30538294
DOI：
    10.1038 / s41388-018-0607-3