乙型肝炎病毒致肝细胞癌发生机制研究进展

doi:10.3969/j.issn.1672-5069.2014.04.031

摘要/Abstract

摘要： 肝细胞癌（HCC）的发生与乙型肝炎病毒（HBV）感染密切相关。HBV感染所致的炎症反应、HBV X基因及其产物X蛋白、核心启动子突变、前S2区突变、剪接特异性蛋白等均可能参与HCC的发生发展。

Abstract: The infection of hepatitis B virus （HBV） plays an important role in the occurrence of hepatocellular carcinoma （HCC）. Multiple factors may be involved in the hepatocarcinogenesis of HBV-related HCC,such as inflammatory response,HBV X gene and its protein,the mutation of HBV core promoter and pre-S 2 genes,HBV spliced protein and so on. We will discuss some progresses in this field.

Key words: Hepatocellular carcinoma, Hepatitis B virus, Mechanisms

郭恩爽综述, 周福元审校. 乙型肝炎病毒致肝细胞癌发生机制研究进展[J]. 实用肝脏病杂志, 2014, 17(4): 437-440.

GuoEnshuang, Zhou Fuyuan. Hepatitis B virus- associated mechanisms of hepatocellular carcinoma[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2014, 17(4): 437-440.

参考文献

[1] Dang HT,Budhu A,Wang XW. The origin of cancer stem cells. J Hepatol,2014,155（2）:384-396.
[2] De Giorgi V,Monaco A,Worchech A,et al. Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma. J Transl Med,2009,7（1）:85.
[3] De Mitri MS,Cassini R,Bernardi M. Hepatitis B virus-related hepatocarcinogenesis:molecular oncogenic potential of clear or occult infections. Eur J Cancer,2010,46（12）:2178-2186.
[4] Chen CF,Lee WC,Yang HI,et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma.Gastroenterology,2011,141（4）:1240-1248.
[5] Wang SH,Yeh SH,Chen PJ. The driving circuit of HBx and androgen receptor in HBV-related hepatocarcinogenesis. Gut,2014,1（1）:1-2.
[6] 王兆文,彭志海,李克,等. p16影响乙型肝炎病毒相关性肝细胞癌的发生. 中华肿瘤杂志,2003,25（4）：356-358.
[7] 刘晓红,林静,曹晓哲,等. 乙型肝炎病毒X蛋白羧基端氨基酸缺失对肝癌细胞学行为的影响.中华医学杂志,2005,85（12）：825-830.
[8] 刘晓红,朱明华,曹晓哲,等. HBx蛋白羧基端缺失对肝癌细胞生物学行为的影响. 癌症,2005,24（10）：1213-1219.
[9] Tu H,Bonura C,Giannini C,et al. Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues. Cancer Res,2001,61（21）:7803-7810.
[10] 林静,朱明华,曲建慧,等. HBx及其羧基末端40个氨基酸对SMMC-7721肝细胞增殖的影响. 中华病理学杂志,2005,34（9）：592-595.
[11] Li J,Xu Z,Zheng Y,et al. Regulation of hepatocyte nuclear factor 1 activity by wildtype and mutant hepatitis B virus X proteins. J Virol,2002,76（12）:5875-5881.
[12] Tang H,Liu L,Liu F,et al. Establishment of cell lines using a doxycycline-inducible gene expression system to regulate expression of hepatitis B virus X protein. Arch Virol,2009,154（7）:1021-1026.
[13] Lee YI. The Hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem,2001,276（20）:16969-16977.
[14] Caselmann WH. Transactivation of cellular gene expression by hepatitis B viral proteins:a possible molecular mechanism of hepatocarcinogenesis. J Hepatol,1995,22（1 Suppl）:34-37.
[15] De Mitri MS,Cassini R,Bernardi M. Hepatitis B virus-related hepatocarcinogenesis:molecular oncogenic potential of clear or occult infections. Eur J Cancer,2010,46（12）:2178-2186.
[16] Brechot C,Kremsdorf D,Soussan P,et al. Hepatitis B virus （HBV）-related hepatocellular carcinoma（HCC）:Molecular mechanisms and novel paradigms. Pathol Biol,2010,58（4）:278-287.
[17] Feitelson M A,Lee J. Hepatitis B virus integration,fragile sites,and hepatocarcinogenesis. Cancer Letters,2007,252（2）:157-170.
[18] Bréchot C,Gozuacik D,Murakami Y,et al. Molecular bases for the development of hepatitis B virus（HBV）-related hepatocellular carcinoma （HCC）. Semin Cancer Biol,2000,10（3）:211-231.
[19] Nguyen DH,Ludgate L,Hu J. Hepatitis B virus-cell interactions and pathogenesis. J Cell Physiol,2008,216（2）:289-294.
[20] 丁浩,何柳兴,冯涛.乙型肝炎病毒X蛋白对人肝细胞内β-catenin定位及转录活性的影响. 基础与临床,2009,29（5）：475-478.
[21] Jung JK,Arora P,Pagano JS,et al. Expression of DNA methyltransferase 1 isactivated by hepatitis B virus X protein via a regulatory circuit involving the p16INK4a-cyclinD1-CDK 4/6-pRb-E2F1 pathway. Cancer Res,2007,67（12）:5771-5778.
[22] Clippinger AJ, Gearhart TL, Bouchard MJ. Hepatitis B virus X protein modulatesapoptosis in primary rat hepatocytes by regulating both NF-kappaB and themitochondrial permeability transition pore. J Virol,2009,83（10）:4718-4731.
[23] Wen Y,Golubkov VS,Strongin AY,et al. Interaction of hepatitis Bviral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation. J Biol Chem,2008,283（5）:2793-2803.
[24] Martin-Lluesma S,Schaeffer C,Robert EI,et al. Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1. Hepatology,2008,48（5）:1467-1476.
[25] Ou DP,Tao YM,Tang FQ,et al. The hepatitis B virus X protein promoteshepatocellular carcinoma metastasis by upregulation of matrix metallopro-teinases. Int J Cancer,2007,120（6）:1208-1214.
[26] Yoo YG,Na TY,Seo HW,et al. Hepatitis B virus X protein induces the expression of MTA1 and HDAC1,which enhances hypoxia signaling in hepatocellular carcinoma cells. Oncogene, 2008,27（24）:3405-3413.
[27] Han HK,Han CY,Cheon EP,et al. Role of hypoxia-inducible factor alpha in hepatitis-B-virus X protein-mediated MDR1 activation. Biochem Biophys Res Commun,2007,357（2）:567-573.
[28] Huang Y,Tong S,Tai AW,et al. Hepatitis B virus core promoter mutations contribute to by hepatocarcinogenesis deregulating SKP2 and its target,p21. Gastroenterology,2011,141（4）:1412-1421.
[29] Teufel A,Maass T,Strand S,et al. Liver-specific Ldb1 deletionresults in enhanced liver cancer development. J Hepatol,2010,53（6）:1078-1084.
[30] Mun H S, Lee SA,Kim H,et al. Novel F141L pre-S2 mutation in hepatitis B virus increases the risk of hepatocellular carcinoma in patients with chronic genotype C infections. J Virol,2011,85（1）:123-132.
[31] 强福林,吴徐明,李海波,等. 乙型肝炎病毒前S2区缺失突变与肝癌相关性研究. 实用癌症杂志,2011,26（1）：20-21.
[32] Hsieh YH,Su IJ,Wang HC,et al. Hepatitis B virus pre-S2 mutant surface antigen induces degradation of cyclin-dependent kinase inhibitor p27kip1 through c-Jun activation domain-binding protein 1. Mol Cancer Res,2007,5（10）:1063-1072.
[33] Mancini-Bourgine M,Bayard F,Soussan P,et al. Hepatitis B virus splice-generated protein induces T-cell responses in HLA-transgenic mice and hepatitis B virus-infected patients. J Virol,2007,81（10）:4963-4972.
[34] Brechot C,Kremsdorf D,Soussan P,et al. Hepatitis B virus （HBV）-related hepatocellular carcinoma（HCC）:Molecular mechanisms and novel paradigms. Pathol Biol,2010,58（4）:278-287.
[35] Squadrito G,Orlando ME, Pollicino T, et al. Virological profiles in patients with chronic hepatitis C and overt or occult HBV infection. Am J Gastroenterol,2002,97（6）:1518-1523.