Aberrant cyclin A expression and centrosome overduplication induced by hepatitis B virus Pre-S2 mutants and its implication in hepatocarcinogenesis
Aberrant cyclin A expression and centrosome overduplication induced by hepatitis B virus Pre-S2 mutants and its implication in hepatocarcinogenesis
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DOI：
10.1093/carcin/bgr296
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发表时间：
2012-02-01
期刊：
影响因子：
4.7
通讯作者：
Su, Ih-Jen
中科院分区：
文献类型：
--
作者：
Wang, Lily Hui-Ching;Huang, Wenya;Su, Ih-Jen
携带B型肝炎病毒（HBV）前S2突变体的毛玻璃样肝细胞被认为是肝细胞癌（HCC）的癌前病变。前S2突变体聚集于内质网（ER），可诱导内质网应激，上调细胞周期蛋白A，促进肝细胞增殖。值得注意的是，细胞周期蛋白A被异常检测到的细胞质，而不是细胞核，前S2突变体转基因小鼠的肝脏，从而提高细胞质细胞周期蛋白A在HBV肝癌发生的潜在作用。在这项研究中，我们证实了细胞周期蛋白A在大多数HBV相关的肝癌组织的细胞质中检测到。在体外，pre-S2 MUR启动的ER应激可以诱导细胞质细胞周期蛋白A介导的切割由钙依赖性蛋白酶mu-calpain，导致在N-末端截短的产品，这是优先位于细胞质中。异常的细胞周期蛋白A表达随后诱导中心体过度复制，这种作用被钙蛋白酶特异性抑制剂或靶向细胞周期蛋白A的RNA干扰所消除。总的来说，我们的数据表明，HBV前S2突变体可能通过ER应激诱导引起异常的细胞周期蛋白A表达和中心体过度复制，从而代表了HBV肝癌发生中染色体不稳定的潜在机制。
Ground glass hepatocytes harboring hepatitis B virus (HBV) pre-S2 mutants have been recognized as pre-neoplastic lesions of hepatocellular carcinoma (HCC). The pre-S2 mutants accumulated in endoplasmic reticulum (ER) can induce ER stress, upregulate cyclin A and promote hepatocyte proliferation. Notably, cyclin A was aberrantly detected in the cytoplasm, instead of nucleus, of pre-S2 mutant-transgenic mice livers, thereby raising the potential role of cytoplasmic cyclin A in HBV hepatocarcinogenesis. In this study, we confirmed that cyclin A was detected in the cytoplasm in the majority of HBV-related HCC tissues. In vitro, the pre-S2 mutant-initiated ER stress could induce cytoplasmic cyclin A mediated via cleavage by the calcium-dependent protease mu-calpain, resulting in an N-terminal truncated product which was preferentially located in the cytoplasm. The aberrant cyclin A expression subsequently induced centrosome overduplication, and this effect was abolished by calpain-specific inhibitors or RNA interference targeting to cyclin A. Overall, our data indicate that HBV pre-S2 mutant may elicit aberrant cyclin A expression and centrosome overduplication through ER stress induction and thereby represent a potential mechanism for the chromosome instability in HBV hepatocarcinogenesis.