Department of Medicine, University of Cape Town, Groote Schuur Hospital, South Africa.
J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:144-52. doi: 10.1111/j.1440-1746.2010.06546.x.
Currently available evidence supports a role for the hepatitis B virus (HBV) x gene and protein in the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). HBx gene is often included, and remains functionally active, in the HBV DNA that is frequently integrated into cellular DNA during hepatocellular carcinogenesis. HBx protein promotes cell cycle progression, inactivates negative growth regulators, and binds to and inhibits the expression of p53 tumour suppressor gene and other tumour suppressor genes and senescence-related factors. However, the molecular mechanisms responsible for HBx protein-induced HCC remain uncertain. Only some of the more fully documented or more recently recognised mechanisms are reviewed. During recent years evidence has accumulated that HBx protein modulates transcription of methyl transferases, causing regional hypermethylation of DNA that results in silencing of tumour suppressor genes, or global hypomethylation that results in chromosomal instability, thereby playing a role in hepatocarcinogenesis. HBx protein has both anti-apoptotic and pro-apoptotic actions, apparently contradictory effects that have yet to be explained. Particularly important among the anti-apoptotic properties is inhibition of p53. Recent experimental observations suggest that HBx protein may increase the expression of TERT and telomerase activity, prolonging the life-span of hepatocytes and contributing to malignant transformation. The protein also interferes with nucleotide excision repair through both p53-dependent and p53- independent mechanisms. Carboxy-terminal truncated HBx protein loses its inhibitory effects on cell proliferation and pro-apoptotic properties, and it may enhance the protein's ability to transform oncogenes. Dysregulation of IGF-II enhances proliferation and anti-apoptotic effects of oncogenes, resulting in uncontrolled cell growth.
目前的证据支持乙型肝炎病毒 (HBV) x 基因和蛋白在 HBV 诱导的肝细胞癌 (HCC) 发病机制中的作用。HBx 基因通常包含在 HBV DNA 中，并且在肝细胞癌变过程中经常整合到细胞 DNA 中仍然具有功能活性。HBx 蛋白促进细胞周期进程，使负性生长调节剂失活，并与 p53 肿瘤抑制基因和其他肿瘤抑制基因以及衰老相关因子结合并抑制其表达。然而，HBx 蛋白诱导 HCC 的分子机制仍不确定。仅综述了一些记录更完整或最近才认识到的机制。近年来，有证据表明 HBx 蛋白调节甲基转移酶的转录，导致 DNA 的局部高甲基化，从而导致肿瘤抑制基因沉默，或导致全局低甲基化，从而导致染色体不稳定，从而在肝癌发生中发挥作用。HBx 蛋白具有抗凋亡和促凋亡作用，这显然是相互矛盾的作用，尚未得到解释。在抗凋亡特性中特别重要的是对 p53 的抑制作用。最近的实验观察表明，HBx 蛋白可能会增加 TERT 的表达和端粒酶活性，延长肝细胞的寿命并促进恶性转化。该蛋白还通过 p53 依赖性和 p53 非依赖性机制干扰核苷酸切除修复。羧基末端截断的 HBx 蛋白失去其对细胞增殖和促凋亡特性的抑制作用，并且可能增强该蛋白转化致癌基因的能力。IGF-II 的失调增强了致癌基因的增殖和抗凋亡作用，导致不受控制的细胞生长。
