Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver.
Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver.
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DOI：
10.1038/s41467-020-20572-8
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发表时间：
2021-01-28
影响因子：
16.6
通讯作者：
Chao HW
中科院分区：
文献类型：
--
作者：
Lin H;Huang YS;Fustin JM;Doi M;Chen H;Lai HH;Lin SH;Lee YL;King PC;Hou HS;Chen HW;Young PY;Chao HW
肝细胞癌是肝脏最主要的原发恶性肿瘤。基因毒性和遗传学模型已经揭示了肝癌细胞来源于肝细胞，但肿瘤灶出现的关键区域在哪里以及这种转化是如何发生的仍不清楚。在这里，肝细胞围绕小叶中心(CL)区域的超多倍体被证明与二乙基亚硝胺治疗后肝细胞癌的发展密切相关。我们发现CL区域是超多倍体肝细胞聚集和癌前病变形成的主要小叶。我们还证明了Aurkb的上调在促进超多倍化中起着关键作用。在胞质分裂过程中，AURKB在中体上的磷酸化增加，导致脱落失败和超多倍化。AURKB的药理抑制显著减少了二乙基亚硝胺处理的肝脏CL区周围的核大小和肿瘤灶数。我们的工作揭示了CL肝细胞的病理性超多倍体与转化为肝癌细胞之间的密切分子联系。多倍体是正常肝细胞的常见特征，但超多倍体的病理生理功能尚不清楚。在这里，作者表明，遗传毒性应激诱导超多倍体肝细胞在肝小叶中心区周围聚集，这可能表明癌前病变的形成。
Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells. Polyploidy is a common feature in normal hepatocytes, however, the pathophysiological function of hepatic hyperpolyploidy is unclear. Here, the authors show that genotoxic stress induces accumulation of hyperpolyploid hepatocytes around the centrilobular region of the liver, which may indicate the origin of preneoplastic formation.