载脂蛋白A1亚型比例的改变促进男性慢性乙型肝炎的进展
|
摘要
乙型肝炎严重威胁着人类的健康,据统计全世界的乙肝病毒携带者有3.5亿之众。而乙肝病毒携带者一旦发展为慢性乙肝,就很可能恶变为肝硬化和肝细胞性肝癌。在慢性乙型肝炎进展为肝硬化、肝细胞癌的进程中,男性患者进展的速度比女性快,流行病学调查结果显示男性及绝经后女性更易患慢性乙肝相关性肝硬化及肝癌。因此我们认为在感染了乙肝病毒后,男、女性慢性乙肝患者在向肝硬化及肝癌演变过程中有着本质的区别,而对这种疾病进展的性别差异目前还没有一致的解释机制。
为探索不同性别中慢性乙型肝炎疾病进展差异的机制,我们采用双向荧光差异凝胶电泳(two-dimensional difference gel electrophoresis,2-D DIGE)的方法分别比较雌、雄HBV转基因鼠与同性别C57BL／6小鼠的肝脏组织中蛋白质表达的差异,结果显示载脂蛋白A-I (Apo A-I, apolipoprotein A-I)总表达量在雌、雄HBV转基因鼠肝组织中均下降。由于血循环中Apo A-I的水平与慢性乙肝及其相关原发性肝细胞癌相关,低水平的Apo A-I提示有严重的肝损伤,因此我们发现雌雄HBV转基因鼠肝中Apo A-I表达下调,可能是因为HBV在体内抗原表达引起肝细胞损伤并扰乱肝细胞脂质代谢。
更有趣的是,我们使用2-D western blotting方法研究HBV转基因鼠肝组织及慢性乙肝病人血清中Apo A-I的表达,发现Apo A-I的亚型3表达量在雄性HBV转基因鼠肝组织及男性慢性乙肝病人血清中均有明显增加,而雌性转基因鼠肝组织及女性病人血清中Apo A-I的各亚型比例均无明显改变。Apo A-I主要在肝脏中合成并被认为存在翻译后修饰。雄性HBV转基因鼠肝脏及男性慢性乙肝病人血清中Apo A-I各亚型表达量比例的改变反映了不同的亚型有其不同的翻译后修饰,因此他们的功能和特征也不同。
近来研究发现在慢性乙肝相关性肝癌患者及肝癌转基因鼠模型的血清中存在高浓度的氧化型Apo A-I。我们进一步的实验结果显示在雄性转基因鼠肝组织及男性病人血清中增加的Apo A-I的亚型3为氧化修饰型Apo A-I,而女性却没有,可能是因为女性体内的雌激素及其衍生物的作用使Apo A-I的氧化过程被阻断或减弱。因此雄性HBV转基因鼠肝脏及慢性乙肝病人血清中Apo A-I亚型3的升高可能为男性乙型肝炎进展较女性更快的现象提供新的思路。
以上这些结果提示慢性乙肝病毒感染扰乱了Apo A-I亚型比例,进而阻碍了Apo A-I整体功能的发挥。因此,我们认为这种选择性氧化修饰的Apo A-I亚型可作为病理标志用于进一步研究慢性乙肝的发病机制；而在临床上,Apo A-I亚型的特异性抗体结合其他传统标志物可用于慢性乙肝的预后评估。
Chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). One interesting feature of CHB-related HCC is the male predominance, with a male-to-female ratio of 5-7:1. There is similar or even more pronounced gender disparity in hepatitis B virus (HBV) transgenic mouse models. All these facts indicate that HBV influences the function of male and female host cells in different ways. The mechanisms that account for this gender disparity remain unclear. We need some new points of view and methods to study this problem.
In this study, we focused on 6-8-week-old male and female HBV-transgenic (HBV-Tg) mouse liver, which represents the typical age at which early pathological lesions are detectable. Because of the great sensitivity and dynamic range that are afforded by fluorescent tags Cy2, Cy3 and Cy5, two-dimensional difference gel electrophoresis (2-D DIGE) can give much greater accuracy of quantization. To obtain more insight into the underlying mechanisms of the gender disparity of CHB progression,2-D DIGE was employed to compare the liver proteome of C57BL/6 and HBV-Tg mice in males and females.
We identified 8 differently expressed proteins in male HBV-Tg mice and 12 in female HBV-Tg mice. Apolipoprotein A-I (Apo A-I) was found to be down-regulated in male and female HBV-Tg mouse liver., which indicated that HBV antigen expression in vivo might cause liver cell injury and disturb liver cell lipid metabolism.
HBV can affect liver cell lipid metabolism in male and female HBV-Tg mice, but there are some interesting differences between the two sexes. Our results indicated that HBV antigen expression-mediated Apo A-I alteration occurred not only in its total protein expression level but also in the pattern of Apo A-I isoform expression in male HBV-Tg mouse liver, whereas we did not find any changes in the pattern of Apo A-I isoform expression in female HBV-Tg mouse liver. Furthermore, we got accordant results in male and female CHB patient sera, but did not in CHC patient sera. Apo A-I is initially synthesized as a preproprotein and can be modificated at the post-translation level。The heterogeneous alteration of the pattern of Apo A-I isoform expression in male HBV-Tg mouse liver reflects different post-translational regulation of different isoforms of Apo A-I, which may be correlated with specific features or functions of the isoforms.
Finally, we found that the oxidized Apo A-I was increased in male HBV-Tg mouse liver and the increase in the Apo A-I isoform 3 in liver of male HBV-Tg mice may represent a highly oxidized Apo A-I isoform. This process of over-oxidizing Apo A-I may be blocked or deduced by estradiol or its derivatives in female HBV-Tg mouse liver. The different pattern of Apo A-I isoforms observed in male and female transgenic mouse liver may be the result of an interaction between oxidative stress induced by HBV antigen expression and sex hormones in vivo. The increase in Apo A-I isoform 3 in male HBV-Tg mouse liver and CHB patient serum may provide a new clue to explain the male gender susceptibility to CHB progression.
Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, the selectively modified Apo A-I isoforms may be considered to be a pathological hallmark that could extend our knowledge of the molecular pathogenesis of CHB. Development of antibodies that specifically recognize the isoforms of Apo A-I may prove to be useful, in combination with other traditional markers, as a more efficient way to evaluate the prognosis of CHB.
为探索不同性别中慢性乙型肝炎疾病进展差异的机制,我们采用双向荧光差异凝胶电泳(two-dimensional difference gel electrophoresis,2-D DIGE)的方法分别比较雌、雄HBV转基因鼠与同性别C57BL／6小鼠的肝脏组织中蛋白质表达的差异,结果显示载脂蛋白A-I (Apo A-I, apolipoprotein A-I)总表达量在雌、雄HBV转基因鼠肝组织中均下降。由于血循环中Apo A-I的水平与慢性乙肝及其相关原发性肝细胞癌相关,低水平的Apo A-I提示有严重的肝损伤,因此我们发现雌雄HBV转基因鼠肝中Apo A-I表达下调,可能是因为HBV在体内抗原表达引起肝细胞损伤并扰乱肝细胞脂质代谢。
更有趣的是,我们使用2-D western blotting方法研究HBV转基因鼠肝组织及慢性乙肝病人血清中Apo A-I的表达,发现Apo A-I的亚型3表达量在雄性HBV转基因鼠肝组织及男性慢性乙肝病人血清中均有明显增加,而雌性转基因鼠肝组织及女性病人血清中Apo A-I的各亚型比例均无明显改变。Apo A-I主要在肝脏中合成并被认为存在翻译后修饰。雄性HBV转基因鼠肝脏及男性慢性乙肝病人血清中Apo A-I各亚型表达量比例的改变反映了不同的亚型有其不同的翻译后修饰,因此他们的功能和特征也不同。
近来研究发现在慢性乙肝相关性肝癌患者及肝癌转基因鼠模型的血清中存在高浓度的氧化型Apo A-I。我们进一步的实验结果显示在雄性转基因鼠肝组织及男性病人血清中增加的Apo A-I的亚型3为氧化修饰型Apo A-I,而女性却没有,可能是因为女性体内的雌激素及其衍生物的作用使Apo A-I的氧化过程被阻断或减弱。因此雄性HBV转基因鼠肝脏及慢性乙肝病人血清中Apo A-I亚型3的升高可能为男性乙型肝炎进展较女性更快的现象提供新的思路。
以上这些结果提示慢性乙肝病毒感染扰乱了Apo A-I亚型比例,进而阻碍了Apo A-I整体功能的发挥。因此,我们认为这种选择性氧化修饰的Apo A-I亚型可作为病理标志用于进一步研究慢性乙肝的发病机制；而在临床上,Apo A-I亚型的特异性抗体结合其他传统标志物可用于慢性乙肝的预后评估。
Chronic hepatitis B (CHB) is a major risk factor for hepatocellular carcinoma (HCC). One interesting feature of CHB-related HCC is the male predominance, with a male-to-female ratio of 5-7:1. There is similar or even more pronounced gender disparity in hepatitis B virus (HBV) transgenic mouse models. All these facts indicate that HBV influences the function of male and female host cells in different ways. The mechanisms that account for this gender disparity remain unclear. We need some new points of view and methods to study this problem.
In this study, we focused on 6-8-week-old male and female HBV-transgenic (HBV-Tg) mouse liver, which represents the typical age at which early pathological lesions are detectable. Because of the great sensitivity and dynamic range that are afforded by fluorescent tags Cy2, Cy3 and Cy5, two-dimensional difference gel electrophoresis (2-D DIGE) can give much greater accuracy of quantization. To obtain more insight into the underlying mechanisms of the gender disparity of CHB progression,2-D DIGE was employed to compare the liver proteome of C57BL/6 and HBV-Tg mice in males and females.
We identified 8 differently expressed proteins in male HBV-Tg mice and 12 in female HBV-Tg mice. Apolipoprotein A-I (Apo A-I) was found to be down-regulated in male and female HBV-Tg mouse liver., which indicated that HBV antigen expression in vivo might cause liver cell injury and disturb liver cell lipid metabolism.
HBV can affect liver cell lipid metabolism in male and female HBV-Tg mice, but there are some interesting differences between the two sexes. Our results indicated that HBV antigen expression-mediated Apo A-I alteration occurred not only in its total protein expression level but also in the pattern of Apo A-I isoform expression in male HBV-Tg mouse liver, whereas we did not find any changes in the pattern of Apo A-I isoform expression in female HBV-Tg mouse liver. Furthermore, we got accordant results in male and female CHB patient sera, but did not in CHC patient sera. Apo A-I is initially synthesized as a preproprotein and can be modificated at the post-translation level。The heterogeneous alteration of the pattern of Apo A-I isoform expression in male HBV-Tg mouse liver reflects different post-translational regulation of different isoforms of Apo A-I, which may be correlated with specific features or functions of the isoforms.
Finally, we found that the oxidized Apo A-I was increased in male HBV-Tg mouse liver and the increase in the Apo A-I isoform 3 in liver of male HBV-Tg mice may represent a highly oxidized Apo A-I isoform. This process of over-oxidizing Apo A-I may be blocked or deduced by estradiol or its derivatives in female HBV-Tg mouse liver. The different pattern of Apo A-I isoforms observed in male and female transgenic mouse liver may be the result of an interaction between oxidative stress induced by HBV antigen expression and sex hormones in vivo. The increase in Apo A-I isoform 3 in male HBV-Tg mouse liver and CHB patient serum may provide a new clue to explain the male gender susceptibility to CHB progression.
Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, the selectively modified Apo A-I isoforms may be considered to be a pathological hallmark that could extend our knowledge of the molecular pathogenesis of CHB. Development of antibodies that specifically recognize the isoforms of Apo A-I may prove to be useful, in combination with other traditional markers, as a more efficient way to evaluate the prognosis of CHB.
引文
[1]. Popper, H.; Shafritz, D. A.; Hoofnagle, J. H., Relation of the hepatitis B virus carrier state to hepatocellular carcinoma. Hepatology 1987,7, (4),764-72.
[2]. Yuen, M. F.; Tanaka, Y.; Fong, D. Y.; Fung, J.; Wong, D. K.; Yuen, J. C.; But, D. Y.; Chan, A. O.; Wong, B. C.; Mizokami, M.; Lai, C. L., Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol 2008,50(1):7-9..
[3]. McMahon, B. J.; Alberts, S. R.; Wainwright, R. B.; Bulkow, L.; Lanier, A. P., Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska native carriers. Arch Intern Med 1990,150, (5),1051-4.
[4]. Yu, M. W.; Chen, C. J., Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol 1994,17, (2),71-91.
[5]. Lee, C. M.; Lu, S. N.; Changchien, C. S.; Yeh, C. T.; Hsu, T. T.; Tang, J. H.; Wang, J. H.; Lin, D. Y.; Chen, C. L.; Chen, W. J., Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer 1999,86, (7),1143-50.
[6]. Wang, Y.; Cui, F.; Lv, Y.; Li, C.; Xu, X.; Deng, C.; Wang, D.; Sun, Y.; Hu, G.; Lang, Z.; Huang, C.; Yang, X., HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004,39, (2),318-24.
[7]. Rogers, A. B.; Theve, E. J.; Feng, Y.; Fry, R. C.; Taghizadeh, K.; Clapp, K. M.; Boussahmain, C.; Cormier, K. S.; Fox, J. G., Hepatocellular carcinoma associated with liver-gender disruption in male mice. Cancer Res 2007,67, (24),11536-46.
[8]. Yu, M. W.; Cheng, S. W.; Lin, M. W.; Yang, S. Y.; Liaw, Y. F.; Chang, H. G.; Hsiao, T. J.; Lin, S. M.; Lee, S. D.; Chen, P. J.; Liu, C. J.; Chen, C. J., Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst 2000,92, (24),2023-8.
[9]. Yeh, S. H.; Chang, C. F.; Shau, W. Y.; Chen, Y. W.; Hsu, H. C.; Lee, P. H.; Chen, D. S.; Chen, P. J., Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis. Cancer Res 2002,62, (15),4346-51.
[10].Deng, G.; Zhou, G.; Zhai, Y.; Li, S.; Li, X.; Li, Y.; Zhang, R.; Yao, Z.; Shen, Y.; Qiang, B.; Wang, Y.; He, F., Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004,40, (2),318-26.
[11].Han, J.; Ding, L.; Yuan, B.; Yang, X.; Wang, X.; Li, J.; Lu, Q.; Huang, C.; Ye, Q., Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells. Nucleic Acids Res 2006,34, (10),3095-106.
[12].Naugler, W. E.; Sakurai, T.; Kim, S.; Maeda, S.; Kim, K.; Elsharkawy, A. M.; Karin, M., Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007, 317,(5834),121-4.
[13].Chiu, C. M.; Yeh, S. H.; Chen, P. J.; Kuo, T. J.; Chang, C. J.; Chen, P. J.; Yang, W. J.; Chen, D. S., Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci U S A 2007,104, (8),2571-8.
[14].Narayan R, Gangadharan B, Hantz O, Antrobus R, Garcia A, Dwek RA, et al. Proteomic analysis of HepaRG cells, a novel cell line that supports hepatitis B virus infection. J Proteome Res 2009; 8:118-122.
[15].Saigo, K.; Yoshida, K.; Ikeda, R.; Sakamoto, Y.; Murakami, Y.; Urashima, T.; Asano, T.; Kenmochi, T.; Inoue, I., Integration of hepatitis B virus DNA into the myeloid/lymphoid or mixed-lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma. Hum Mutat 2008,29, (5),703-8.
[16]. Wang, J.; Jiang, D.; Zhang, H.; Lv, S.; Rao, H.; Fei, R.; Wei, L., Proteome responses to stable hepatitis B virus transfection and following interferon alpha treatment in human liver cell line HepG2. Proteomics 2009,9, (6),1672-82.
[17]. Yang, F.; Yan, S.; He, Y.; Wang, F.; Song, S.; Guo, Y.; Zhou, Q.; Wang, Y.; Lin, Z.; Yang, Y.; Zhang, W.; Sun, S., Expression of hepatitis B virus proteins in transgenic mice alters lipid metabolism and induces oxidative stress in the liver. J Hepatol 2008,48, (1),12-9.
[18].Timms, J. F.; Cramer, R., Difference gel electrophoresis. Proteomics 2008,8, (23-24),4886-97.
[19].Ren, J.; Wang, L.; Chen, Z.; Ma, Z. M.; Zhu, H. G.; Yang, D. L.; Li, X. Y.; Wang, B. I.; Fei, J.; Wang, Z. G.; Wen, Y. M., Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy. J Med Virol 2006,78, (5),551-60.
[20].Nisar S, Lane CS, Wilderspin AF, Welham KJ, Griffiths WJ, Patterson LH. A proteomic approach to the identification of cytochrome P450 isoforms in male and female rat liver by nanoscale liquid chromatography-electrospray ionization-tandem mass spectrometry. Drug Metab Dispos 2004;32:382-6.
[21].Lauderback, C. M.; Hackett, J. M.; Huang, F. F.; Keller, J. N.; Szweda, L. I.; Markesbery, W. R.; Butterfield, D. A., The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain:the role of Abetal-42. J Neurochem 2001;78:413-416.
[22].Perluigi, M.; Giorgi, A.; Blarzino, C; De Marco, F.; Foppoli, C; Di Domenico,
[23].F.; Butterfield, D. A.; Schinina, M. E.; Cini, C; Coccia, R., Proteomics analysis
[24]. of protein expression and specific protein oxidation in human papillomavirus
[25].transformed keratinocytes upon UVB irradiation. J Cell Mol Med 2008.
[26].Aldred, S.; Sozzi, T.; Mudway, I.; Grant, M. M.; Neubert, H.; Kelly, F. J.; Griffiths, H. R., Alpha tocopherol supplementation elevates plasma apolipoprotein Al isoforms in normal healthy subjects. Proteomics 2006,6, (5),1695-703.
[27].Beg, Z. H.; Stonik, J. A.; Hoeg, J. M.; Demosky, S. J., Jr.; Fairwell, T.; Brewer, H. B., Jr., Human apolipoprotein A-I. Post-translational modification by covalent phosphorylation. J Biol Chem 1989, 264, (12),6913-21.
[28].Contiero, E.; Ferrari, R.; Vaselli, G. M.; Folin, M., Apolipoprotein AI isoforms in serum determined by isoelectric focusing and immunoblotting. Electrophoresis 1997,18, (1),122-6.
[29].Ai, J.; Tan, Y.; Ying, W.; Hong, Y.; Liu, S.; Wu, M.; Qian, X.; Wang, H., Proteome analysis of hepatocellular carcinoma by laser capture microdissection. Proteomics 2006,6, (2),538-46.
[30].He, Q. Y.; Lau, G. K.; Zhou, Y.; Yuen, S. T.; Lin, M. C.; Kung, H. F.; Chiu, J. F., Serum biomarkers of hepatitis B virus infected liver inflammation:a proteomic study. Proteomics 2003,3, (5),666-74.
[31].Norton, P. A.; Gong, Q.; Mehta, A. S.; Lu, X.; Block, T. M., Hepatitis B virus-mediated changes of apolipoprotein mRNA abundance in cultured hepatoma cells. J Virol 2003,77, (9),5503-6.
[32]. Kim, K.; Kim, K. H.; Kim, H. H.; Cheong, J., Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRalpha. Biochem J 2008,416, (2),219-30.
[33].Kim, K. H.; Shin, H. J.; Kim, K.; Choi, H. M.; Rhee, S. H.; Moon, H. B.; Kim, H. H.; Yang, U. S.; Yu, D. Y.; Cheong, J., Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma. Gastroenterology 2007,132, (5),1955-67.
[34].Na, T. Y.; Shin, Y. K.; Roh, K. J.; Kang, S. A.; Hong, I.; Oh, S. J.; Seong, J. K.; Park, C. K.; Choi, Y. L.; Lee, M. O., Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2009,49, (4),1122-31.
[35].Hoeg, J. M.; Meng, M. S.; Ronan, R.; Fairwell, T.; Brewer, H. B., Jr., Human apolipoprotein A-I. Post-translational modification by fatty acid acylation. J Biol Chem 1986,261, (9),3911-4.
[36].Fernandez-Irigoyen, J.; Santamaria, E.; Sesma, L.; Munoz, J.; Riezu, J. I.; Caballeria, J.; Lu, S. C.; Prieto, J.; Mato, J. M.; Avila, M. A.; Corrales, F. J., Oxidation of specific methionine and tryptophan residues of apolipoprotein A-I in hepatocarcinogenesis. Proteomics 2005,5, (18), 4964-72.
[37].Hsieh, Y. H.; Su, I. J.; Wang, H. C.; Chang, W. W.; Lei, H. Y.; Lai, M. D.; Chang, W. T.; Huang, W., Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 2004,25, (10),2023-32.
[38].Severi, T.; Ying, C.; Vermeesch, J. R.; Cassiman, D.; Cnops, L.; Verslype, C.; Fevery, J.; Arckens, L.; Neyts, J.; van Pelt, J. F., Hepatitis B virus replication causes oxidative stress in HepAD38 liver cells. Mol Cell Biochem 2006,290, (1-2),79-85.
[39].Yoshino K, Komura S, Watanabe I, Nakagawa Y, Yagi K. Effect of estrogens on serum and liver lipid peroxide levels in mice. J Clin Biochem Nutr 1987; 3:233-239.
[40].Lacort, M.; Leal, A. M.; Liza, M.; Martin, C.; Martinez, R.; Ruiz-Larrea, M. B., Protective effect of estrogens and catecholestrogens against peroxidative membrane damage in vitro. Lipids 1995, 30,(2),141-6.
[41].Inoue, H.; Shimizu, I.; Lu, G.; Itonaga, M.; Cui, X.; Okamura, Y.; Shono, M.; Honda, H.; Inoue, S.; Muramatsu, M.; Ito, S., Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes. Dig Dis Sci 2003,48, (3),570-80.
[42].Omoya, T.; Shimizu, I.; Zhou, Y.; Okamura, Y.; Inoue, H.; Lu, G.; Itonaga, M.; Honda, H.; Nomura, M.; Ito, S., Effects of idoxifene and estradiol on NF-kappaB activation in cultured rat hepatocytes undergoing oxidative stress. Liver 2001,21, (3),183-91.
[43].3. Ishizaka N, Ishizaka Y, Takahashi E, Toda Ei E, Hashimoto H, Ohno M, Nagai R, Yamakado M. Increased prevalence of carotid atherosclerosis in hepatitis B virus carriers. Circulation 2002;105:1028-30.
[44].Targher G, Bertolini L, Padovani R, Rodella S, Arcaro G, Day C. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol 2007;46:1126-32.
[1].史鸣树,闵建荣。乙肝病毒性肝炎。北京：人民军医出版社,2009.8
[2]. Lavanchy D.Hepatitis B virus epidemiology, disease burden, treatment, and current and emerg in prevention and control measures. J Viral Hepatol 2004,11:97-107
[3]. Chu CM,Karayiannis P,Fowler MJF,etal.Natural history of chronic hepatitis B virus infection inTaiwan.studies of hepatitis B virus DNA in serum.Hepatology 1985,5:431-34
[4]. Hsu YS,Chien RN,Ych CT,etal.Long-term outcome after spontaneous HBcAg sero conversion in patients with chronic hepatitis B.Hepatology.2002,35:1522-27
[5]. Fattovich G,Olivari N,Pasino M,etal.Long-term outcome of chronic hepatitis B in Caucasian patients:mortality after 25 years.Gut.2008,57:84-90
[6]. Liaw YF,Leung N,Kao JH,etal.Asian-pacific Consensus statement on the management of chronic hepatitis B;2008 update.hepatol Int.2008,2:263-83
[7]. Liaw YF, ed.Asia-Pacific Pocket Guide to Hepatitis B.New Jersey:University of Wiscons in Board of Regents and MDG Development Group.2006
[8]. Lai Cl,Ratziu V.Yuen MF,etal.Viral hepatitis B.Lancet.2003,362:2089-94
[9]. El-Serag HB,Rudolph KL.Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76.
[10]. Yu MW,Chen CJ (1994) Crit Rev Oncol Hematol 17:71-91.
[11].龙丽,单可人,任锡麟。雌激素受体基因多态性与疾病相关性的研究进展。国际遗传学杂志2008年4月15日第31卷第2期IntJGenetApr.15,2008,Vol.31,No.2
[12].Naugler WE,Sakurai T,Kim S,etal.Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.Science 2007;317:121-4.
[13].Ahnpg Y,Klein A,Adler R,etal.Estrogen suppresses hepatitis B virus expression in male athymic mice transplanted with HBV transfected HepG-2 cells.Antiviral Res,1992,19;285-293.
[14].Tur-Kaspa R,Shaul Y,Moore DD,etal.The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology, 1988,167:630-633.
[15].VillaE, CamettiniL, DuganiA, etal. CancerRes,1995,55:498-500
[16].VillaE, DuganiA, MolesA, etal. Hepatology,1998,27(4):983—988)
[17].VillaE, MolesA, Ferrettil, etal. Hepatology,2000,32(2):233.238
[18].lavaroneM, LamperticoP, SelettiC, etal. Cancer。2003。 98(3): 529-534
[19].VillaE, DuganiA, FantoniE, etal. CancerRes。 1996,56:3883.3885
[20].VillaE. Ferrettil, ButtafuocoP。 etal. BrJCancer,2001,84:881.885
[21].VillaE. GrottolaA, ColantoniA, etal. AnnNYAcadSci,2002,963:37.45
[22].ZhangQ, HilsenbeckS, FuquaS, etal. J Steroid Biochem Mol Biol,1996,59:251.260
[23].VillaE, ColantoniA, GrottolaA, etal. Mol Cell Endocrinol,2002。 193(1-2):6569
[24]. Yu I.Nagatu N,Makino Y,et.al.Effect of androgens and their manipulation on cell growth and androgen receptor(AR) levels in AR — positive and negative human hepatocellular carcinoma. Hepatol,1995,2Z(3):295～30Z.
[25].Yu MW, Yang YC, Yang SY, etal. Androgen receptor exon CAG repeat length and risk of hepatocellular carcinoma in women. Hepatology,2002,36:156.163.
[26].Carruda G, Cocciadiferro L, Bellavia V, etal. Intercellular Communication and Human Hepatocellular Carcinoma. Ann NY Acad Sci.2004,1028:202-212.
[27].Yu MW,Chen CJ.Elevated serum testosterone levels and risk of hepatocellular carcinoma. CancerRes,1993,53:790
[28]. Yu L,Nagasue N,Yamaguchi M,etal.Effects of castration and Androgen replacement on tumour growth of human hepatocellular carcinoma in nudemice.J Hepatol,1996 Sep;25(3):362-9.
[29].Ciocca DR,Jorge AD,Jorge O,etal.Estrogen receptors, progesterone receptors and heat-shock 27-kD protein in liver biopsy specimens from patients with hepatitis B virus infection 1991May;13(5):838-44Hepatology
[30].Cho H,Lim IK.Expression of androgen receptor and its implication in hepatoma cells.CancerLett,1997 May19;115(2):135-40
[31].Chi-MingChiu,Shiou-HweiYeh,Pei-JerChen etal. Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci USA.2007Feb20; 104(8):2571-8.
[32].Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GRETCH). Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology 2004;40:1361-9.
[33].Arlin B. Rogersl,2, Elizabeth J etal. Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice. Cancer Research 67,11536-11546, December 15,2007.
[34].刘耳,张宝初,吴燕 等.高发区肝癌与乙型肝炎病毒感染的血清学分析及临床意义[J].石河子医学院学报,1991,13(3)t183
[35].白威,刘月香.综述.原发性肝癌的发病与HBV感染及性别的关系.肿瘤研究与临床2002年6月第14卷第3期
[36].陈建国,朱源英.肝癌的流行病学与预防战略高发区的研究与效果初评[J].中国肿瘤,1994,3(5)：18-20.
[37].孙怡予,综述.酒精性肝病发病机制的研究进展.国外医学消化系疾病分艇,1999,1(2)：7.
[38].梁酉,罗国银,黄太秀等。荤素膳食与癌症的流行病学的调查[J].中国肿瘤,1994.3(7)：22—23.
[39].Rogers, A. B.; Theve, E. J.; Feng, Y.; Fry, R. C.; Taghizadeh, K.; Clapp, K. M.; Boussahmain, C.; Cormier, K. S.; Fox, J. G., Hepatocellular carcinoma associated with liver-gender disruption in male mice. Cancer Res 2007,67, (24),11536-46.
[40].Wang, Y.; Cui, F.; Lv, Y.; Li, C.; Xu, X.; Deng, C.; Wang, D.; Sun, Y.; Hu, G.; Lang, Z.; Huang, C.; Yang, X., HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004,39, (2),318-24.
[41].Yu, M. W.; Cheng, S. W.; Lin, M. W.; Yang, S. Y.; Liaw, Y. F.; Chang, H. C.; Hsiao, T. J.; Lin, S. M.; Lee, S. D.; Chen, P. J.; Liu, C. J.; Chen, C. J., Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst 2000,92, (24),2023-8.
[42].[Yeh, S. H.; Chang, C. F.; Shau, W. Y.; Chen, Y. W.; Hsu, H. C.; Lee, P. H.; Chen, D. S.; Chen, P. J., Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis. Cancer Res 2002,62, (15),4346-51.
[43].Deng, G.; Zhou, G.; Zhai, Y.; Li, S.; Li, X.; Li, Y.; Zhang, R.; Yao, Z.; Shen, Y.; Qiang, B.; Wang, Y.; He, F., Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004,40, (2),318-26.
[44].Han, J.; Ding, L.; Yuan, B.; Yang, X.; Wang, X.; Li, J.; Lu, Q.; Huang, C.; Ye, Q., Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells. Nucleic Acids Res 2006,34, (10),3095-106.
[45].Naugler, W. E.; Sakurai, T.; Kim, S.; Maeda, S.; Kim, K.; Elsharkawy, A. M.; Karin, M., Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007, 317,(5834),121-4.
[2]. Yuen, M. F.; Tanaka, Y.; Fong, D. Y.; Fung, J.; Wong, D. K.; Yuen, J. C.; But, D. Y.; Chan, A. O.; Wong, B. C.; Mizokami, M.; Lai, C. L., Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol 2008,50(1):7-9..
[3]. McMahon, B. J.; Alberts, S. R.; Wainwright, R. B.; Bulkow, L.; Lanier, A. P., Hepatitis B-related sequelae. Prospective study in 1400 hepatitis B surface antigen-positive Alaska native carriers. Arch Intern Med 1990,150, (5),1051-4.
[4]. Yu, M. W.; Chen, C. J., Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol 1994,17, (2),71-91.
[5]. Lee, C. M.; Lu, S. N.; Changchien, C. S.; Yeh, C. T.; Hsu, T. T.; Tang, J. H.; Wang, J. H.; Lin, D. Y.; Chen, C. L.; Chen, W. J., Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection. Cancer 1999,86, (7),1143-50.
[6]. Wang, Y.; Cui, F.; Lv, Y.; Li, C.; Xu, X.; Deng, C.; Wang, D.; Sun, Y.; Hu, G.; Lang, Z.; Huang, C.; Yang, X., HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004,39, (2),318-24.
[7]. Rogers, A. B.; Theve, E. J.; Feng, Y.; Fry, R. C.; Taghizadeh, K.; Clapp, K. M.; Boussahmain, C.; Cormier, K. S.; Fox, J. G., Hepatocellular carcinoma associated with liver-gender disruption in male mice. Cancer Res 2007,67, (24),11536-46.
[8]. Yu, M. W.; Cheng, S. W.; Lin, M. W.; Yang, S. Y.; Liaw, Y. F.; Chang, H. G.; Hsiao, T. J.; Lin, S. M.; Lee, S. D.; Chen, P. J.; Liu, C. J.; Chen, C. J., Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst 2000,92, (24),2023-8.
[9]. Yeh, S. H.; Chang, C. F.; Shau, W. Y.; Chen, Y. W.; Hsu, H. C.; Lee, P. H.; Chen, D. S.; Chen, P. J., Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis. Cancer Res 2002,62, (15),4346-51.
[10].Deng, G.; Zhou, G.; Zhai, Y.; Li, S.; Li, X.; Li, Y.; Zhang, R.; Yao, Z.; Shen, Y.; Qiang, B.; Wang, Y.; He, F., Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004,40, (2),318-26.
[11].Han, J.; Ding, L.; Yuan, B.; Yang, X.; Wang, X.; Li, J.; Lu, Q.; Huang, C.; Ye, Q., Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells. Nucleic Acids Res 2006,34, (10),3095-106.
[12].Naugler, W. E.; Sakurai, T.; Kim, S.; Maeda, S.; Kim, K.; Elsharkawy, A. M.; Karin, M., Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007, 317,(5834),121-4.
[13].Chiu, C. M.; Yeh, S. H.; Chen, P. J.; Kuo, T. J.; Chang, C. J.; Chen, P. J.; Yang, W. J.; Chen, D. S., Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci U S A 2007,104, (8),2571-8.
[14].Narayan R, Gangadharan B, Hantz O, Antrobus R, Garcia A, Dwek RA, et al. Proteomic analysis of HepaRG cells, a novel cell line that supports hepatitis B virus infection. J Proteome Res 2009; 8:118-122.
[15].Saigo, K.; Yoshida, K.; Ikeda, R.; Sakamoto, Y.; Murakami, Y.; Urashima, T.; Asano, T.; Kenmochi, T.; Inoue, I., Integration of hepatitis B virus DNA into the myeloid/lymphoid or mixed-lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma. Hum Mutat 2008,29, (5),703-8.
[16]. Wang, J.; Jiang, D.; Zhang, H.; Lv, S.; Rao, H.; Fei, R.; Wei, L., Proteome responses to stable hepatitis B virus transfection and following interferon alpha treatment in human liver cell line HepG2. Proteomics 2009,9, (6),1672-82.
[17]. Yang, F.; Yan, S.; He, Y.; Wang, F.; Song, S.; Guo, Y.; Zhou, Q.; Wang, Y.; Lin, Z.; Yang, Y.; Zhang, W.; Sun, S., Expression of hepatitis B virus proteins in transgenic mice alters lipid metabolism and induces oxidative stress in the liver. J Hepatol 2008,48, (1),12-9.
[18].Timms, J. F.; Cramer, R., Difference gel electrophoresis. Proteomics 2008,8, (23-24),4886-97.
[19].Ren, J.; Wang, L.; Chen, Z.; Ma, Z. M.; Zhu, H. G.; Yang, D. L.; Li, X. Y.; Wang, B. I.; Fei, J.; Wang, Z. G.; Wen, Y. M., Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy. J Med Virol 2006,78, (5),551-60.
[20].Nisar S, Lane CS, Wilderspin AF, Welham KJ, Griffiths WJ, Patterson LH. A proteomic approach to the identification of cytochrome P450 isoforms in male and female rat liver by nanoscale liquid chromatography-electrospray ionization-tandem mass spectrometry. Drug Metab Dispos 2004;32:382-6.
[21].Lauderback, C. M.; Hackett, J. M.; Huang, F. F.; Keller, J. N.; Szweda, L. I.; Markesbery, W. R.; Butterfield, D. A., The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain:the role of Abetal-42. J Neurochem 2001;78:413-416.
[22].Perluigi, M.; Giorgi, A.; Blarzino, C; De Marco, F.; Foppoli, C; Di Domenico,
[23].F.; Butterfield, D. A.; Schinina, M. E.; Cini, C; Coccia, R., Proteomics analysis
[24]. of protein expression and specific protein oxidation in human papillomavirus
[25].transformed keratinocytes upon UVB irradiation. J Cell Mol Med 2008.
[26].Aldred, S.; Sozzi, T.; Mudway, I.; Grant, M. M.; Neubert, H.; Kelly, F. J.; Griffiths, H. R., Alpha tocopherol supplementation elevates plasma apolipoprotein Al isoforms in normal healthy subjects. Proteomics 2006,6, (5),1695-703.
[27].Beg, Z. H.; Stonik, J. A.; Hoeg, J. M.; Demosky, S. J., Jr.; Fairwell, T.; Brewer, H. B., Jr., Human apolipoprotein A-I. Post-translational modification by covalent phosphorylation. J Biol Chem 1989, 264, (12),6913-21.
[28].Contiero, E.; Ferrari, R.; Vaselli, G. M.; Folin, M., Apolipoprotein AI isoforms in serum determined by isoelectric focusing and immunoblotting. Electrophoresis 1997,18, (1),122-6.
[29].Ai, J.; Tan, Y.; Ying, W.; Hong, Y.; Liu, S.; Wu, M.; Qian, X.; Wang, H., Proteome analysis of hepatocellular carcinoma by laser capture microdissection. Proteomics 2006,6, (2),538-46.
[30].He, Q. Y.; Lau, G. K.; Zhou, Y.; Yuen, S. T.; Lin, M. C.; Kung, H. F.; Chiu, J. F., Serum biomarkers of hepatitis B virus infected liver inflammation:a proteomic study. Proteomics 2003,3, (5),666-74.
[31].Norton, P. A.; Gong, Q.; Mehta, A. S.; Lu, X.; Block, T. M., Hepatitis B virus-mediated changes of apolipoprotein mRNA abundance in cultured hepatoma cells. J Virol 2003,77, (9),5503-6.
[32]. Kim, K.; Kim, K. H.; Kim, H. H.; Cheong, J., Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRalpha. Biochem J 2008,416, (2),219-30.
[33].Kim, K. H.; Shin, H. J.; Kim, K.; Choi, H. M.; Rhee, S. H.; Moon, H. B.; Kim, H. H.; Yang, U. S.; Yu, D. Y.; Cheong, J., Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma. Gastroenterology 2007,132, (5),1955-67.
[34].Na, T. Y.; Shin, Y. K.; Roh, K. J.; Kang, S. A.; Hong, I.; Oh, S. J.; Seong, J. K.; Park, C. K.; Choi, Y. L.; Lee, M. O., Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2009,49, (4),1122-31.
[35].Hoeg, J. M.; Meng, M. S.; Ronan, R.; Fairwell, T.; Brewer, H. B., Jr., Human apolipoprotein A-I. Post-translational modification by fatty acid acylation. J Biol Chem 1986,261, (9),3911-4.
[36].Fernandez-Irigoyen, J.; Santamaria, E.; Sesma, L.; Munoz, J.; Riezu, J. I.; Caballeria, J.; Lu, S. C.; Prieto, J.; Mato, J. M.; Avila, M. A.; Corrales, F. J., Oxidation of specific methionine and tryptophan residues of apolipoprotein A-I in hepatocarcinogenesis. Proteomics 2005,5, (18), 4964-72.
[37].Hsieh, Y. H.; Su, I. J.; Wang, H. C.; Chang, W. W.; Lei, H. Y.; Lai, M. D.; Chang, W. T.; Huang, W., Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 2004,25, (10),2023-32.
[38].Severi, T.; Ying, C.; Vermeesch, J. R.; Cassiman, D.; Cnops, L.; Verslype, C.; Fevery, J.; Arckens, L.; Neyts, J.; van Pelt, J. F., Hepatitis B virus replication causes oxidative stress in HepAD38 liver cells. Mol Cell Biochem 2006,290, (1-2),79-85.
[39].Yoshino K, Komura S, Watanabe I, Nakagawa Y, Yagi K. Effect of estrogens on serum and liver lipid peroxide levels in mice. J Clin Biochem Nutr 1987; 3:233-239.
[40].Lacort, M.; Leal, A. M.; Liza, M.; Martin, C.; Martinez, R.; Ruiz-Larrea, M. B., Protective effect of estrogens and catecholestrogens against peroxidative membrane damage in vitro. Lipids 1995, 30,(2),141-6.
[41].Inoue, H.; Shimizu, I.; Lu, G.; Itonaga, M.; Cui, X.; Okamura, Y.; Shono, M.; Honda, H.; Inoue, S.; Muramatsu, M.; Ito, S., Idoxifene and estradiol enhance antiapoptotic activity through estrogen receptor-beta in cultured rat hepatocytes. Dig Dis Sci 2003,48, (3),570-80.
[42].Omoya, T.; Shimizu, I.; Zhou, Y.; Okamura, Y.; Inoue, H.; Lu, G.; Itonaga, M.; Honda, H.; Nomura, M.; Ito, S., Effects of idoxifene and estradiol on NF-kappaB activation in cultured rat hepatocytes undergoing oxidative stress. Liver 2001,21, (3),183-91.
[43].3. Ishizaka N, Ishizaka Y, Takahashi E, Toda Ei E, Hashimoto H, Ohno M, Nagai R, Yamakado M. Increased prevalence of carotid atherosclerosis in hepatitis B virus carriers. Circulation 2002;105:1028-30.
[44].Targher G, Bertolini L, Padovani R, Rodella S, Arcaro G, Day C. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. J Hepatol 2007;46:1126-32.
[1].史鸣树,闵建荣。乙肝病毒性肝炎。北京：人民军医出版社,2009.8
[2]. Lavanchy D.Hepatitis B virus epidemiology, disease burden, treatment, and current and emerg in prevention and control measures. J Viral Hepatol 2004,11:97-107
[3]. Chu CM,Karayiannis P,Fowler MJF,etal.Natural history of chronic hepatitis B virus infection inTaiwan.studies of hepatitis B virus DNA in serum.Hepatology 1985,5:431-34
[4]. Hsu YS,Chien RN,Ych CT,etal.Long-term outcome after spontaneous HBcAg sero conversion in patients with chronic hepatitis B.Hepatology.2002,35:1522-27
[5]. Fattovich G,Olivari N,Pasino M,etal.Long-term outcome of chronic hepatitis B in Caucasian patients:mortality after 25 years.Gut.2008,57:84-90
[6]. Liaw YF,Leung N,Kao JH,etal.Asian-pacific Consensus statement on the management of chronic hepatitis B;2008 update.hepatol Int.2008,2:263-83
[7]. Liaw YF, ed.Asia-Pacific Pocket Guide to Hepatitis B.New Jersey:University of Wiscons in Board of Regents and MDG Development Group.2006
[8]. Lai Cl,Ratziu V.Yuen MF,etal.Viral hepatitis B.Lancet.2003,362:2089-94
[9]. El-Serag HB,Rudolph KL.Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76.
[10]. Yu MW,Chen CJ (1994) Crit Rev Oncol Hematol 17:71-91.
[11].龙丽,单可人,任锡麟。雌激素受体基因多态性与疾病相关性的研究进展。国际遗传学杂志2008年4月15日第31卷第2期IntJGenetApr.15,2008,Vol.31,No.2
[12].Naugler WE,Sakurai T,Kim S,etal.Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production.Science 2007;317:121-4.
[13].Ahnpg Y,Klein A,Adler R,etal.Estrogen suppresses hepatitis B virus expression in male athymic mice transplanted with HBV transfected HepG-2 cells.Antiviral Res,1992,19;285-293.
[14].Tur-Kaspa R,Shaul Y,Moore DD,etal.The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology, 1988,167:630-633.
[15].VillaE, CamettiniL, DuganiA, etal. CancerRes,1995,55:498-500
[16].VillaE, DuganiA, MolesA, etal. Hepatology,1998,27(4):983—988)
[17].VillaE, MolesA, Ferrettil, etal. Hepatology,2000,32(2):233.238
[18].lavaroneM, LamperticoP, SelettiC, etal. Cancer。2003。 98(3): 529-534
[19].VillaE, DuganiA, FantoniE, etal. CancerRes。 1996,56:3883.3885
[20].VillaE. Ferrettil, ButtafuocoP。 etal. BrJCancer,2001,84:881.885
[21].VillaE. GrottolaA, ColantoniA, etal. AnnNYAcadSci,2002,963:37.45
[22].ZhangQ, HilsenbeckS, FuquaS, etal. J Steroid Biochem Mol Biol,1996,59:251.260
[23].VillaE, ColantoniA, GrottolaA, etal. Mol Cell Endocrinol,2002。 193(1-2):6569
[24]. Yu I.Nagatu N,Makino Y,et.al.Effect of androgens and their manipulation on cell growth and androgen receptor(AR) levels in AR — positive and negative human hepatocellular carcinoma. Hepatol,1995,2Z(3):295～30Z.
[25].Yu MW, Yang YC, Yang SY, etal. Androgen receptor exon CAG repeat length and risk of hepatocellular carcinoma in women. Hepatology,2002,36:156.163.
[26].Carruda G, Cocciadiferro L, Bellavia V, etal. Intercellular Communication and Human Hepatocellular Carcinoma. Ann NY Acad Sci.2004,1028:202-212.
[27].Yu MW,Chen CJ.Elevated serum testosterone levels and risk of hepatocellular carcinoma. CancerRes,1993,53:790
[28]. Yu L,Nagasue N,Yamaguchi M,etal.Effects of castration and Androgen replacement on tumour growth of human hepatocellular carcinoma in nudemice.J Hepatol,1996 Sep;25(3):362-9.
[29].Ciocca DR,Jorge AD,Jorge O,etal.Estrogen receptors, progesterone receptors and heat-shock 27-kD protein in liver biopsy specimens from patients with hepatitis B virus infection 1991May;13(5):838-44Hepatology
[30].Cho H,Lim IK.Expression of androgen receptor and its implication in hepatoma cells.CancerLett,1997 May19;115(2):135-40
[31].Chi-MingChiu,Shiou-HweiYeh,Pei-JerChen etal. Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad Sci USA.2007Feb20; 104(8):2571-8.
[32].Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GRETCH). Randomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifen. Hepatology 2004;40:1361-9.
[33].Arlin B. Rogersl,2, Elizabeth J etal. Hepatocellular Carcinoma Associated with Liver-Gender Disruption in Male Mice. Cancer Research 67,11536-11546, December 15,2007.
[34].刘耳,张宝初,吴燕 等.高发区肝癌与乙型肝炎病毒感染的血清学分析及临床意义[J].石河子医学院学报,1991,13(3)t183
[35].白威,刘月香.综述.原发性肝癌的发病与HBV感染及性别的关系.肿瘤研究与临床2002年6月第14卷第3期
[36].陈建国,朱源英.肝癌的流行病学与预防战略高发区的研究与效果初评[J].中国肿瘤,1994,3(5)：18-20.
[37].孙怡予,综述.酒精性肝病发病机制的研究进展.国外医学消化系疾病分艇,1999,1(2)：7.
[38].梁酉,罗国银,黄太秀等。荤素膳食与癌症的流行病学的调查[J].中国肿瘤,1994.3(7)：22—23.
[39].Rogers, A. B.; Theve, E. J.; Feng, Y.; Fry, R. C.; Taghizadeh, K.; Clapp, K. M.; Boussahmain, C.; Cormier, K. S.; Fox, J. G., Hepatocellular carcinoma associated with liver-gender disruption in male mice. Cancer Res 2007,67, (24),11536-46.
[40].Wang, Y.; Cui, F.; Lv, Y.; Li, C.; Xu, X.; Deng, C.; Wang, D.; Sun, Y.; Hu, G.; Lang, Z.; Huang, C.; Yang, X., HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004,39, (2),318-24.
[41].Yu, M. W.; Cheng, S. W.; Lin, M. W.; Yang, S. Y.; Liaw, Y. F.; Chang, H. C.; Hsiao, T. J.; Lin, S. M.; Lee, S. D.; Chen, P. J.; Liu, C. J.; Chen, C. J., Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma. J Natl Cancer Inst 2000,92, (24),2023-8.
[42].[Yeh, S. H.; Chang, C. F.; Shau, W. Y.; Chen, Y. W.; Hsu, H. C.; Lee, P. H.; Chen, D. S.; Chen, P. J., Dominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesis. Cancer Res 2002,62, (15),4346-51.
[43].Deng, G.; Zhou, G.; Zhai, Y.; Li, S.; Li, X.; Li, Y.; Zhang, R.; Yao, Z.; Shen, Y.; Qiang, B.; Wang, Y.; He, F., Association of estrogen receptor alpha polymorphisms with susceptibility to chronic hepatitis B virus infection. Hepatology 2004,40, (2),318-26.
[44].Han, J.; Ding, L.; Yuan, B.; Yang, X.; Wang, X.; Li, J.; Lu, Q.; Huang, C.; Ye, Q., Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells. Nucleic Acids Res 2006,34, (10),3095-106.
[45].Naugler, W. E.; Sakurai, T.; Kim, S.; Maeda, S.; Kim, K.; Elsharkawy, A. M.; Karin, M., Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007, 317,(5834),121-4.