Nat Commun:肝细胞多倍体化诱导肝细胞癌癌前病变的发生

2021-02-05 xiaozeng MedSci原创

肝细胞癌(HCC)是肝脏中最主要的原发性恶性肿瘤,占所有肝癌病例的90%,其特征为患者的存活率低。

肝细胞癌(HCC)是肝脏中最主要的原发性恶性肿瘤,占所有肝癌病例的90%,其特征为患者的存活率低。遗传毒性和相关遗传模型研究显示,HCC细胞源自于肝细胞,虽然关于HCC细胞起源的相关证据越来越多,但目前尚不清楚肿瘤灶出现的关键区域以及发生这种转化的原因。

既往研究已提出多倍体化在肿瘤发生过程中起着至关重要的作用。大多数哺乳动物是二倍体,但是在特定器官中有着多倍体的发生,如在发育过程中的肝脏中。在产后发育过程中,肝细胞通过无收缩环形成的不完全胞质分裂逐步发展为多倍体,这也是多倍体肝细胞产生的主要机制。


生理性的肝细胞多倍化是肝稳态的多样性因素,也是限制细胞增殖和促进肿瘤抑制作用的相关机制。而由慢性压力或暴露于致癌物所引起的病理性多倍体的产生对癌症发生发展的贡献还有待研究。

在DEN处理过的肝脏中CL和ML区域出现了超多倍体肝细胞

在该研究中,研究人员证实了在经过二乙基亚硝胺(DEN)处理后,小叶(CL)区域周围的肝细胞的超多倍体化与HCC细胞的发生发展密切相关。


研究人员确定了CL区域为超多倍体肝细胞积累和肿瘤前肿瘤灶形成的优势小叶。进一步的研究证明,Aurkb基因的表达水平上调在促进细胞的超多倍体化中起着关键作用。

超多倍体肝细胞产生癌前病变的示意图

在胞质分裂过程中,在中间体中检测到了AURKB蛋白的磷酸化水平的上调,导致细胞分裂的失败和多倍体化的产生。在二乙基亚硝胺处理的肝脏中,对AURKB的药理学抑制作用能够显著降低CL区域周围的细胞核大小和肿瘤灶数量。


总而言之,该研究结果揭示了CL区域的肝细胞病理性多倍体与HCC细胞转化之间密切的分子联系。


原始出处:

Lin, H., Huang, YS., Fustin, JM. et al. Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver. Nat Commun 12, 645 (28 January 2021).

 

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    2021-04-13 xjy02
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    2021-03-30 liuli5079
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