Matsuda Yasunobu, Ichida Takafumi
Department of Medical Technology, Niigata University Graduate School of Health Sciences, Niigata, 951-8518, Japan.
Med Mol Morphol. 2009 Sep;42(3):138-42. doi: 10.1007/s00795-009-0457-8. Epub 2009 Sep 26.
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. The main HCC-associated diseases are chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), and HBV-associated HCC is still prevalent in Asia. Many studies have suggested that HBV X protein (HBX), which is the most common ORF integrated into the host genome, plays a crucial role in hepatocarcinogenesis. However, the accumulated evidence regarding HBX-mediated signaling pathways is not concordant, and it is difficult to understand the mechanistic nature of HBX-associated hepatocarcinogenesis. For example, HBX was reported to inactivate the early responses to DNA damage via p53-dependent and -independent pathways by interacting with several DNA damage-binding proteins and was also reported to sensitize cells to p53-mediated apoptosis via ataxia-telangiectasia and Rad3-related (ATR)-dependent signaling. HBX also interferes with the centrosome replication process, resulting in rearrangement of chromosomes with micronuclei. Moreover, HBX was found to sensitize protein kinases such as Ras/Raf/mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), stress-activated protein kinase/NH2-terminal-Jun kinase (SAPK/JNK), protein kinase B (PKB/Akt), and Janus kinase/STAT (JAK/STAT), indicating that a variety of signaling pathways may be activated by HBX. In this review, we focus on the roles of HBX in DNA damage repair during HCC development, with a view to achieving a better understanding of the significance of HBX in the early steps of hepatocarcinogenesis.
肝细胞癌（HCC）是全球最常见且致命的癌症之一。与HCC相关的主要疾病是乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）的慢性感染，且HBV相关的HCC在亚洲仍然很普遍。许多研究表明，HBV X蛋白（HBX）是整合到宿主基因组中最常见的开放阅读框，在肝癌发生中起关键作用。然而，关于HBX介导的信号通路的累积证据并不一致，难以理解HBX相关肝癌发生的机制本质。例如，据报道HBX通过与几种DNA损伤结合蛋白相互作用，通过p53依赖和非依赖途径使对DNA损伤的早期反应失活，还据报道通过共济失调毛细血管扩张症和Rad3相关（ATR）依赖信号使细胞对p53介导的凋亡敏感。HBX还干扰中心体复制过程，导致染色体与微核重排。此外，发现HBX使诸如Ras/Raf/丝裂原活化蛋白激酶（MAPK）、细胞外信号调节激酶（ERK）、应激激活蛋白激酶/NH2末端-Jun激酶（SAPK/JNK）、蛋白激酶B（PKB/Akt）和Janus激酶/信号转导和转录激活因子（JAK/STAT）等蛋白激酶敏感，表明多种信号通路可能被HBX激活。在本综述中，我们聚焦于HBX在HCC发生过程中DNA损伤修复中的作用，以期更好地理解HBX在肝癌发生早期阶段的意义。
