线粒体sirtuin 4的肿瘤抑制作用在乙型肝炎病毒相关肝细胞癌

StephenW

Tumor suppressive role of mitochondrial sirtuin 4 in induction of G2/M cell cycle arrest and apoptosis in hepatitis B virus-related hepatocellular carcinoma
Fung-Yu Huang #  1 , Danny Ka-Ho Wong #  1   2 , Wai-Kay Seto  1   2 , Lung-Yi Mak  1   2 , Tan-To Cheung  2   3 , Man-Fung Yuen  4   5
Affiliations
Affiliations

    1
    Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
    2
    State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China.
    3
    Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
    4
    Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China. [email protected].
    5
    State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China. [email protected].

#
Contributed equally.

    PMID: 33931611 DOI: 10.1038/s41420-021-00470-8

Abstract

Hepatocellular carcinoma (HCC) is developed from uncontrolled cell growth after the malignant transformation of hepatocytes. The hepatitis B virus (HBV) X protein (HBx) has shown to induce cell cycle progression and hepatocarcinogenesis. A sub-fraction of HBx is localized in the mitochondria. Sirtuin 4 (SIRT4), a mitochondrial protein, has been demonstrated to play a tumor-suppressive role in many cancers, including HCC. However, little is known about the association between mitochondrial HBx and SIRT4 during hepatocarcinogenesis. We aimed to investigate the clinical significance and functional role of SIRT4 in HBV-related HCC. SIRT4 expression was significantly lower in the HCC tissues collected from 30 patients with HBV-related HCC than in normal liver tissues from control patients (p < 0.0001). TCGA data analysis indicated that SIRT4 expression was also lower in patients with HBV infection than in those without, and SIRT4 levels were positively associated with better patient survival. Similarly, HCC cell lines had lower SIRT4 expression than normal liver cell lines (all p < 0.01). Among the HCC cell lines, those harbored HBV had a lower SIRT4 expression than those without HBV (p < 0.0001). In vitro experiments revealed that stable HBx transfection suppressed SIRT4 expression in both HepG2 and Huh7 cells (both p < 0.001). Ectopic SIRT4 overexpression alone could induce cellular senescence through arresting cell-cycle progression at G2/M, and inducing cell apoptosis in HCC cells. Mechanistically, SIRT4 upregulated cell-cycle governing genes p16 and p21 protein expression, suppressed CyclinB1/Cdc2 and Cdc25c which normally induce cell-cycle progression, and suppressed survivin to induce apoptosis. Our findings demonstrate the interaction between HBV and SIRT4 in the context of HCC. SIRT4 involves in G2/M DNA damage checkpoint control and genomic stability in hepatocarcinogenesis, which could be targeted for future anticancer strategies.

StephenW

线粒体sirtuin 4的肿瘤抑制作用在乙型肝炎病毒相关肝细胞癌的G2 / M细胞周期阻滞和凋亡诱导中的作用
黄凤玉＃1，黄嘉豪＃1 2，怀基濑户1 2，麦龙Y 1 2，陈德To 2 3，袁文峰4 5
隶属关系
隶属关系

    1个
    香港大学，香港特别行政区玛丽医院，香港大学医学系。
    2个
    中国香港特别行政区香港大学肝脏研究国家重点实验室。
    3
    中国香港特别行政区玛丽医院，香港大学外科。
    4
    香港大学，香港特别行政区玛丽医院，香港大学医学系。 [email protected]。
    5
    中国香港特别行政区香港大学肝脏研究国家重点实验室。 [email protected]。

＃
贡献均等。

    PMID：33931611 DOI：10.1038 / s41420-021-00470-8

抽象的

肝细胞恶性转化后，不受控制的细胞生长会发展为肝细胞癌（HCC）。乙型肝炎病毒（HBV）X蛋白（HBx）已显示出诱导细胞周期进程和肝癌发生的能力。 HBx的一个子部分位于线粒体中。 Sirtuin 4（SIRT4）是一种线粒体蛋白，已被证明在包括HCC在内的许多癌症中具有肿瘤抑制作用。但是，关于肝癌发生过程中线粒体HBx和SIRT4之间的关联知之甚少。我们旨在调查SIRT4在乙肝相关肝癌中的临床意义和功能作用。在30例HBV相关性HCC患者的HCC组织中，SIRT4的表达明显低于对照患者的正常肝组织（p <0.0001）。 TCGA数据分析表明，HBV感染患者的SIRT4表达也低于未感染者，并且SIRT4水平与患者更好的生存呈正相关。同样，HCC细胞株的SIRT4表达低于正常肝细胞株（所有p <0.01）。在HCC细胞系中，带有HBV的细胞的SIRT4表达低于没有HBV的细胞（p <0.0001）。体外实验表明，稳定的HBx转染抑制了HepG2和Huh7细胞中SIRT4的表达（均p <0.001）。单独的异位SIRT4过表达可以通过在G2 / M处阻止细胞周期进程并诱导HCC细胞凋亡来诱导细胞衰老。从机制上讲，SIRT4上调了细胞周期调控基因p16和p21蛋白的表达，抑制了通常诱导细胞周期进程的CyclinB1 / Cdc2和Cdc25c，并抑制了survivin诱导了细胞凋亡。我们的发现证明了在HCC背景下HBV和SIRT4之间的相互作用。 SIRT4参与肝癌发生过程中的G2 / M DNA损伤检查点控制和基因组稳定性，这可能是未来抗癌策略的目标。