Mani Saravana Kumar Kailasam, Andrisani Ourania
Department of Basic Medical Sciences and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
Genes (Basel). 2018 Mar 2;9(3):137. doi: 10.3390/genes9030137.
Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery. Understanding how hCSCs form will enable development of therapeutic strategies to prevent their formation. Recent studies have identified an epigenetic mechanism involving the downregulation of the chromatin modifying Polycomb Repressive Complex 2 (PRC2) during HBV infection, which results in re-expression of hCSC marker genes in infected hepatocytes and HBV-associated liver tumors. However, the genesis of hCSCs requires, in addition to the expression of hCSC markers cellular changes, rewiring of metabolism, cell survival, escape from programmed cell death, and immune evasion. How these changes occur in chronically HBV-infected hepatocytes is not yet understood. In this review, we will present the basics about HBV infection and hepatocarcinogenesis. Next, we will discuss studies describing the mutational landscape of liver cancers and how epigenetic mechanisms likely orchestrate cellular reprograming of hepatocytes to enable formation of hCSCs.
慢性乙型肝炎病毒（HBV）感染与肝细胞癌（HCC）的发病机制相关。尽管有HBV疫苗，但目前针对HCC的治疗仍不充分。全球有2.57亿人是慢性HBV携带者，HBV感染母亲所生的儿童会成为慢性携带者，注定会发展为肝癌。因此，需要新的治疗方法来靶向HCC发病机制中涉及的关键通路。越来越多的证据支持肝癌干细胞（hCSCs）的存在，它们导致化疗耐药以及治疗或手术后癌症复发。了解hCSCs如何形成将有助于开发预防其形成的治疗策略。最近的研究发现了一种表观遗传机制，即在HBV感染期间，染色质修饰的多梳抑制复合体2（PRC2）下调，这导致感染的肝细胞和HBV相关肝肿瘤中hCSC标记基因重新表达。然而，hCSCs的产生除了需要hCSC标记物的表达外，还需要细胞变化、代谢重编程、细胞存活、逃避程序性细胞死亡和免疫逃逸。目前尚不清楚这些变化在慢性HBV感染的肝细胞中是如何发生的。在这篇综述中，我们将介绍HBV感染和肝癌发生的基础知识。接下来，我们将讨论描述肝癌突变图谱的研究，以及表观遗传机制可能如何协调肝细胞的细胞重编程以促成hCSCs的形成。
