乙型肝炎病毒X蛋白（HBx）对Notch1与Snail的调控及其功能的研究
摘要
早在1970年,Sherlock等人的研究发现在慢性肝脏疾病和原发性肝细胞癌患者血清中存在肝炎相关澳大利亚抗原,由此提示慢性乙型肝炎病毒(hepatitis B virus,HBV)感染与肝细胞癌(hepatocellular carcinoma, HCC)发生存在关联。到1981年,Beasley等人通过对中国台湾地区22,707例男性的前瞻性人群调查发现乙型肝炎病毒表面抗原(hepatitis B surface antigen, HBsAg)携带者较非HBsAg携带者罹患HCC的风险高出63倍,由此为HBV感染与HCC发生的关联提供强有力的证据。
在HBV基因组编码的所有蛋白中,乙型肝炎病毒X蛋白(hepatitis B virus X protein,HBx)作为一个重要的非结构多功能调节蛋白在病毒感染、复制、致病和致癌过程中发挥重要作用。尽管已有部分研究证实HBx可通过影响细胞本身信号通路来激活癌基因信号在HBV相关肝癌发生(HBV-associated hepatocarcinogenesis)过程中可能发挥重要的促进肿瘤发生的作用,然而对于HBx在HBV相关肝癌(HBV-associated hepatocellular carcinoma, HBV-HCC)发生发展过程中的作用仍有许多不明之处。
已有研究发现作为一个进化上高度保守的局部信号传导通路,Notch1信号在肝癌发生过程中可能发挥抑制肿瘤形成的作用,但是在HBV相关肝癌发生过程中HBx表达与Notch1信号之间的相互作用及其机制仍有待阐明。此外在慢性HBV感染的HCC患者中发现有较高的肿瘤复发和转移率,尽管近年来HBx与HBV相关肝癌发生的病理相关和重要性引起诸多关注,但是对于HBx在肿瘤侵袭和转移中的作用及其机制目前不甚明了,而本研究主要围绕HBx在HBV相关肝癌发生发展和侵袭转移中的作用及其机制展开。
在本研究的第一部分,发现在正常肝细胞系和肝癌细胞系中表达HBx可下调内源性的Notch1胞内活性片段(Notch1 intracellular domain, ICN1)蛋白水平及其下游靶基因的mRNA水平。进一步研究发现HBx对Notch1信号通路的负调控是通过减少Notch1的剪切而不是抑制Notch1转录或者其配体表达水平来实现的,而且HBx下调Notch1剪切的作用是经由抑制参与Notch1剪切的γ-分泌酶(γ-secretase)的关键组分presenilinl (Psen1)来介导的。通过HBx瞬时转染实验发现,在体外细胞培养中HBx可通过下调ICN1水平来促进肝癌细胞增殖(cell proliferation)、诱导肝癌细胞G1-S期的细胞周期进展(G1-S cell cycle progression)和抑制细胞衰老(cellular senescence)。进一步用裸鼠皮下肿瘤移植实验证实稳转HBx也可经由下调ICN1水平钝化衰老样生长抑制(senescence-like growth arrest)从而促进肝癌细胞生长和肿瘤形成。最后在HBV相关肝癌患者肿瘤组织样本中证实了下调的Psen1-依赖的Notch1信号和钝化的衰老样生长抑制二者之间的相关性。结论：这部分研究阐明了HBx在肝癌发生过程中的一个新功能,即通过抑制Notch1信号活化来钝化衰老样生长抑制从而促进肿瘤发生,该发现提供了一种可能的HBV相关肝癌发生的新机制。
在本研究的第二部分,发现在肝癌细胞中表达HBx可使肝癌细胞形态从上皮型转化为间质型、上皮细胞标志分子下调(如E-cadherin)、β-catenin的核转位以及间质细胞标志分子的上调(如N-cadherin、vimentin和fibronectin),由此提示HBx表达可诱导肝癌细胞发生上皮-间质转化(epithelial-mesenchymal transition,EMT)。进一步研究发现HBx诱导发生EMT依赖于EMT调节转录因子Snail蛋白水平的增加,而Snail蛋白水平的增加是通过HBx表达增强Snail蛋白稳定性,而非通过促进Snail转录来实现的,siRNA干扰Snail可以抑制HBx诱导发生EMT。此外还证实HBx表达通过激活PI3K/AKT/GSK-3β信号通路来增强Snail蛋白稳定性,PI3K/AKT信号通路特异性的抑制剂LY294002和Wortmannin处理、以及组成性激活型的GSK-3βS9A突变体共转染均可抑制HBx表达上调Snail蛋白水平。最后通过体外细胞划痕实验、Transwell细胞迁移实验和Collagen细胞侵袭实验分析发现,在体外细胞培养中HBx表达可促进肝癌细胞的细胞迁移(cell migration)和细胞侵袭(cell invasion),而siRNA干扰Snail可以抑制HBx表达增强细胞迁移和细胞侵袭的能力,由此提示HBx表达可能通过诱导肝癌细胞发生EMT从而参与HBV相关肝癌的侵袭和转移过程。结论：这部分研究阐明了HBx在促进HBV相关肝癌发生发展中的一个新功能,即通过激活PI3K/AKT/GSK-3β信号通路来增强肝癌细胞中Snail蛋白稳定性从而诱导发生EMT、增强细胞迁移和侵袭能力,该发现提供了一种可能的HBV相关肝癌患者肿瘤复发和转移的新机制。
As early as 1970, Sherlock and his colleagues found chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum, which indicated the association between chronic hepatitis B virus (HBV) infection and the development of hepatocellular carcinoma (HCC). In 1981, a powerful substantiation of the association between chronic HBV infection and HCC development was the result of a prospective cohort study in which Beasley and his colleagues followed 22, 707 Chinese men in Taiwan (China) and found that incidence of HCC among carriers of HBV surface antigen (HBsAg) is 63 times higher than among HBsAg non-carriers.
Among all proteins encoded by HBV genome, hepatitis B virus X protein (HBx), a key nonstructural multifunctional regulatory protein of the virus, is at the intersection of HBV infection, replication, pathogenesis, and carcinogenesis. Although previous investigations have revealed that HBx might promote HBV-associated hepatocarcinogenesis through activating some oncogenic signal pathways, the role of HBx in the molecular mechanism for the development and progression of HBV-associated hepatocellular carcinoma (HBV-HCC) remains poorly understood.
Although it has been reported that Notch1 signaling, as an evolutionary conserved local cell interaction mechanism, could exert a tumor suppressive function in hepatocarcinogenesis, the interaction between HBx expression and Notch1 signaling remains further elucidation. Besides, a high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of HBx in HBV-associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in tumor invasion and metastasis remain not fully understood.
In the part one of this thesis, we report that HBx expression in hepatic and hepatoma cells resulted in decreased endogenous protein level of Notch1 intracellular domain (ICN1) and mRNA levels of its downstream target genes. These effects were shown due to reduction of Notch1 cleavage by HBx via suppressing presenilin1 (Psen1) transcription rather than inhibiting Notch1 transcription or its ligands expression. By transient HBx expression, decreased ICN1 resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular senescence in vitro. Furthermore, the effect of blunted senescence-like growth arrest by stable HBx expression via suppressing ICN1 was shown in a nude mouse xenograft transplantation model. The correlation of inhibited Psenl-dependent Notchl signaling and blunted senescence-like growth arrest was also observed in HBV-associated HCC patient tumor samples. Our results revealed a novel function of HBx in blunting senescence-like growth arrest through decreasing Notchl signaling, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis.
In the part two of this thesis, we found that HBx expression could induce change of cell morphology from epithelial-like phenotype to mesenchymal-like phenotype, downregulation of epithelial marker expression (e.g. E-cadherin), nuclear translocation of P-catenin, upregulation of mesenchymal marker expression (e.g. N-cadherin, vimentin, and fibronectin), which indicates HBx expression could induce epithelial-mesenchymal transition (EMT) in hepatoma cells. This effect was shown due to increased EMT regulatory transcription factor Snail protein level by HBx transfection through enhancing Snail protein stability rather than upregulating Snail transcription, which could be reversed by siRNA Snail cotransfection with HBx. It was further elucidated HBx expression could enhance Snail protein stability via activating PI3K/AKT/GSK-3P signal pathway, which were substantiated by PI3K specific inhibitor LY294002 and Wortmannin treatment or constitutively active GSK-3βS9A mutant plasmid cotransfection with HBx. Moreover, it was also found that HBx expression in hepatoma cells could enhance cell migration ability and cell invasion ability in vitro, which could be reversed by siRNA Snail cotransfection, through wound healing assay, transwell cell migration assay, and collagen cell invasion assay. These results revealed a novel function of HBx in promoting EMT through stabilizing Snail protein via activating PI3K/AKT/GSK-3βsignaling, thus facilitating cell migration and invasion, which could provide a potential molecular mechanism for tumor invasion and metastasis in HBV-associated HCC patients.
在HBV基因组编码的所有蛋白中,乙型肝炎病毒X蛋白(hepatitis B virus X protein,HBx)作为一个重要的非结构多功能调节蛋白在病毒感染、复制、致病和致癌过程中发挥重要作用。尽管已有部分研究证实HBx可通过影响细胞本身信号通路来激活癌基因信号在HBV相关肝癌发生(HBV-associated hepatocarcinogenesis)过程中可能发挥重要的促进肿瘤发生的作用,然而对于HBx在HBV相关肝癌(HBV-associated hepatocellular carcinoma, HBV-HCC)发生发展过程中的作用仍有许多不明之处。
已有研究发现作为一个进化上高度保守的局部信号传导通路,Notch1信号在肝癌发生过程中可能发挥抑制肿瘤形成的作用,但是在HBV相关肝癌发生过程中HBx表达与Notch1信号之间的相互作用及其机制仍有待阐明。此外在慢性HBV感染的HCC患者中发现有较高的肿瘤复发和转移率,尽管近年来HBx与HBV相关肝癌发生的病理相关和重要性引起诸多关注,但是对于HBx在肿瘤侵袭和转移中的作用及其机制目前不甚明了,而本研究主要围绕HBx在HBV相关肝癌发生发展和侵袭转移中的作用及其机制展开。
在本研究的第一部分,发现在正常肝细胞系和肝癌细胞系中表达HBx可下调内源性的Notch1胞内活性片段(Notch1 intracellular domain, ICN1)蛋白水平及其下游靶基因的mRNA水平。进一步研究发现HBx对Notch1信号通路的负调控是通过减少Notch1的剪切而不是抑制Notch1转录或者其配体表达水平来实现的,而且HBx下调Notch1剪切的作用是经由抑制参与Notch1剪切的γ-分泌酶(γ-secretase)的关键组分presenilinl (Psen1)来介导的。通过HBx瞬时转染实验发现,在体外细胞培养中HBx可通过下调ICN1水平来促进肝癌细胞增殖(cell proliferation)、诱导肝癌细胞G1-S期的细胞周期进展(G1-S cell cycle progression)和抑制细胞衰老(cellular senescence)。进一步用裸鼠皮下肿瘤移植实验证实稳转HBx也可经由下调ICN1水平钝化衰老样生长抑制(senescence-like growth arrest)从而促进肝癌细胞生长和肿瘤形成。最后在HBV相关肝癌患者肿瘤组织样本中证实了下调的Psen1-依赖的Notch1信号和钝化的衰老样生长抑制二者之间的相关性。结论：这部分研究阐明了HBx在肝癌发生过程中的一个新功能,即通过抑制Notch1信号活化来钝化衰老样生长抑制从而促进肿瘤发生,该发现提供了一种可能的HBV相关肝癌发生的新机制。
在本研究的第二部分,发现在肝癌细胞中表达HBx可使肝癌细胞形态从上皮型转化为间质型、上皮细胞标志分子下调(如E-cadherin)、β-catenin的核转位以及间质细胞标志分子的上调(如N-cadherin、vimentin和fibronectin),由此提示HBx表达可诱导肝癌细胞发生上皮-间质转化(epithelial-mesenchymal transition,EMT)。进一步研究发现HBx诱导发生EMT依赖于EMT调节转录因子Snail蛋白水平的增加,而Snail蛋白水平的增加是通过HBx表达增强Snail蛋白稳定性,而非通过促进Snail转录来实现的,siRNA干扰Snail可以抑制HBx诱导发生EMT。此外还证实HBx表达通过激活PI3K/AKT/GSK-3β信号通路来增强Snail蛋白稳定性,PI3K/AKT信号通路特异性的抑制剂LY294002和Wortmannin处理、以及组成性激活型的GSK-3βS9A突变体共转染均可抑制HBx表达上调Snail蛋白水平。最后通过体外细胞划痕实验、Transwell细胞迁移实验和Collagen细胞侵袭实验分析发现,在体外细胞培养中HBx表达可促进肝癌细胞的细胞迁移(cell migration)和细胞侵袭(cell invasion),而siRNA干扰Snail可以抑制HBx表达增强细胞迁移和细胞侵袭的能力,由此提示HBx表达可能通过诱导肝癌细胞发生EMT从而参与HBV相关肝癌的侵袭和转移过程。结论：这部分研究阐明了HBx在促进HBV相关肝癌发生发展中的一个新功能,即通过激活PI3K/AKT/GSK-3β信号通路来增强肝癌细胞中Snail蛋白稳定性从而诱导发生EMT、增强细胞迁移和侵袭能力,该发现提供了一种可能的HBV相关肝癌患者肿瘤复发和转移的新机制。
As early as 1970, Sherlock and his colleagues found chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum, which indicated the association between chronic hepatitis B virus (HBV) infection and the development of hepatocellular carcinoma (HCC). In 1981, a powerful substantiation of the association between chronic HBV infection and HCC development was the result of a prospective cohort study in which Beasley and his colleagues followed 22, 707 Chinese men in Taiwan (China) and found that incidence of HCC among carriers of HBV surface antigen (HBsAg) is 63 times higher than among HBsAg non-carriers.
Among all proteins encoded by HBV genome, hepatitis B virus X protein (HBx), a key nonstructural multifunctional regulatory protein of the virus, is at the intersection of HBV infection, replication, pathogenesis, and carcinogenesis. Although previous investigations have revealed that HBx might promote HBV-associated hepatocarcinogenesis through activating some oncogenic signal pathways, the role of HBx in the molecular mechanism for the development and progression of HBV-associated hepatocellular carcinoma (HBV-HCC) remains poorly understood.
Although it has been reported that Notch1 signaling, as an evolutionary conserved local cell interaction mechanism, could exert a tumor suppressive function in hepatocarcinogenesis, the interaction between HBx expression and Notch1 signaling remains further elucidation. Besides, a high incidence of tumor recurrence and metastasis has been reported in hepatocellular carcinoma (HCC) patients with chronic hepatitis B virus (HBV) infection. Although the pathological relevance and significance of HBx in HBV-associated hepatocarcinogenesis attracted much attention in recent years, the role and molecular mechanism for HBx in tumor invasion and metastasis remain not fully understood.
In the part one of this thesis, we report that HBx expression in hepatic and hepatoma cells resulted in decreased endogenous protein level of Notch1 intracellular domain (ICN1) and mRNA levels of its downstream target genes. These effects were shown due to reduction of Notch1 cleavage by HBx via suppressing presenilin1 (Psen1) transcription rather than inhibiting Notch1 transcription or its ligands expression. By transient HBx expression, decreased ICN1 resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular senescence in vitro. Furthermore, the effect of blunted senescence-like growth arrest by stable HBx expression via suppressing ICN1 was shown in a nude mouse xenograft transplantation model. The correlation of inhibited Psenl-dependent Notchl signaling and blunted senescence-like growth arrest was also observed in HBV-associated HCC patient tumor samples. Our results revealed a novel function of HBx in blunting senescence-like growth arrest through decreasing Notchl signaling, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis.
In the part two of this thesis, we found that HBx expression could induce change of cell morphology from epithelial-like phenotype to mesenchymal-like phenotype, downregulation of epithelial marker expression (e.g. E-cadherin), nuclear translocation of P-catenin, upregulation of mesenchymal marker expression (e.g. N-cadherin, vimentin, and fibronectin), which indicates HBx expression could induce epithelial-mesenchymal transition (EMT) in hepatoma cells. This effect was shown due to increased EMT regulatory transcription factor Snail protein level by HBx transfection through enhancing Snail protein stability rather than upregulating Snail transcription, which could be reversed by siRNA Snail cotransfection with HBx. It was further elucidated HBx expression could enhance Snail protein stability via activating PI3K/AKT/GSK-3P signal pathway, which were substantiated by PI3K specific inhibitor LY294002 and Wortmannin treatment or constitutively active GSK-3βS9A mutant plasmid cotransfection with HBx. Moreover, it was also found that HBx expression in hepatoma cells could enhance cell migration ability and cell invasion ability in vitro, which could be reversed by siRNA Snail cotransfection, through wound healing assay, transwell cell migration assay, and collagen cell invasion assay. These results revealed a novel function of HBx in promoting EMT through stabilizing Snail protein via activating PI3K/AKT/GSK-3βsignaling, thus facilitating cell migration and invasion, which could provide a potential molecular mechanism for tumor invasion and metastasis in HBV-associated HCC patients.
引文
1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533-543.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-156.
3. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-1917.
4. Bruix J, Boix L, Sala M, Llovet JM. Focus on hepatocellular carcinoma. Cancer Cell 2004;5:215-219.
5. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-2576.
6. Boyle P, Levin B. World Cancer Report 2008. Lyon:International Agency for Research on Cancer (IARC),2008.
7. Cancer incidence in five continents. Volume Ⅷ. IARC Sci Publ 2002:1-781.
8. Colombo M, Sangiovanni A. Etiology, natural history and treatment of hepatocellular carcinoma. Antiviral Res 2003;60:145-150.
9. Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2005;9:191-211, v.
10. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis:from genes to environment. Nat Rev Cancer 2006;6:674-687.
11. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31:339-346.
12. Badvie S. Hepatocellular carcinoma. Postgrad Med J 2000;76:4-11.
13. Limdi JK, Crampton JR. Hereditary haemochromatosis. QJM 2004;97:315-324.
14. Sarkany RP. The management of porphyria cutanea tarda. Clin Exp Dermatol 2001;26:225-232.
15. Parfrey H, Mahadeva R, Lomas DA. Alpha(1)-antitrypsin deficiency, liver disease and emphysema. Int J Biochem Cell Biol 2003;35:1009-1014.
16. Tanguay RM, Jorquera R, Poudrier J, St-Louis M. Tyrosine and its catabolites: from disease to cancer. Acta Biochim Pol 1996;43:209-216.
17. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126:460-468.
18. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis. Hepatology 2006;43:S99-S112.
19. Adams LA, Angulo P. Recent concepts in non-alcoholic fatty liver disease. Diabet Med 2005;22:1129-1133.
20. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis 1999;19:271-285.
21. Liaw YF, Tai DI, Chu CM, Lin DY, Sheen IS, Chen TJ, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study. Gastroenterology 1986;90:263-267.
22. Sun Z, Lu P, Gail MH, Pee D, Zhang Q, Ming L, et al. Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 1999;30:379-383.
23. Bruno S, Silini E, Crosignani A, Borzio F, Leandro G, Bono F, et al. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis:a prospective study. Hepatology 1997;25:754-758.
24. Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Tapias JM, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;2:1004-1006.
25. Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675-680.
26. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797-1801.
27. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985;313:1256-1262.
28. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582-592.
29. Sherlock S, Fox RA, Niazi SP, Scheuer PJ. Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1970;1:1243-1247.
30. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004;350:1118-1129.
31. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-1257.
32. Liu J, Fan D. Hepatitis B in China. Lancet 2007;369:1582-1583.
33. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000;64:51-68.
34. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-1745.
35. Lau JY, Wright TL. Molecular virology and pathogenesis of hepatitis B. Lancet 1993;342:1335-1340.
36. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 2004;127:S56-61.
37. Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P. Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol 2000; 10:211-231.
38. Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virus-related hepatocellular carcinoma:paradigms for viral-related human carcinogenesis. Oncogene 2006;25:3823-3833.
39. Cougot D, Neuveut C, Buendia MA. HBV induced carcinogenesis. J Clin Virol 2005;34 Suppl 1:S75-78.
40. Christine N, Yu W, Marie Annick B. Mechanisms of HBV-related hepatocarcinogenesis. Journal of hepatology.
41. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003;22:5093-5107.
42. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004;78:12725-12734.
43. Diao J, Garces R, Richardson CD. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 2001; 12:189-205.
44. Butel JS, Lee TH, Slagle BL. Is the DNA repair system involved in hepatitis-B-virus-mediated hepatocellular carcinogenesis? Trends Microbiol 1996;4:119-124.
45. Cromlish JA. Hepatitis B virus-induced hepatocellular carcinoma:possible roles for HBx. Trends Microbiol 1996;4:270-274.
46. Feitelson MA, Duan LX. Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol 1997;150:1141-1157.
47. Su Q, Schroder CH, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P. Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas. Hepatology 1998;27:1109-1120.
48. Haruna Y, Hayashi N, Katayama K, Yuki N, Kasahara A, Sasaki Y, et al. Expression of X protein and hepatitis B virus replication in chronic hepatitis. Hepatology 1991;13:417-421.
49. Vitvitski-Trepo L, Kay A, Pichoud C, Chevallier P, de Dinechin S, Shamoon BM, et al. Early and frequent detection of HBxAg and/or anti-HBx in hepatitis B virus infection. Hepatology 1990;12:1278-1283.
50. Wang WL, London WT, Lega L, Feitelson MA. HBxAg in the liver from carrier patients with chronic hepatitis and cirrhosis. Hepatology 1991;14:29-37.
51. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991;351:317-320.
52. Zheng Y, Chen WL, Louie SG, Yen TS, Ou JH. Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 2007;45:16-21.
53. Seto E, Mitchell PJ, Yen TS. Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 1990;344:72-74.
54. Maguire HF, Hoeffler JP, Siddiqui A. HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 1991;252:842-844.
55. Wu JY, Zhou ZY, Judd A, Cartwright CA, Robinson WS. The hepatitis B virus-encoded transcriptional trans-activator hbx appears to be a novel protein serine/threonine kinase. Cell 1990;63:687-695.
56. Cha MY, Kim CM, Park YM, Ryu WS. Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology 2004;39:1683-1693.
57. Kew MC. Increasing evidence that hepatitis B virus X gene protein and p53 protein may interact in the pathogenesis of hepatocellular carcinoma. Hepatology 1997;25:1037-1038.
58. Kong HJ, Park MJ, Hong S, Yu HJ, Lee YC, Choi YH, et al. Hepatitis B virus X protein regulates transactivation activity and protein stability of the cancer-amplified transcription coactivator ASC-2. Hepatology 2003;38:1258-1266.
59. Lara-Pezzi E, Majano PL, Gomez-Gonzalo M, Garcia-Monzon C, Moreno-Otero R, Levrero M, et al. The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes. Hepatology 1998;28:1013-1021.
60. Lian Z, Liu J, Li L, Li X, Clayton M, Wu MC, et al. Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of beta-catenin. Hepatology 2006;43:415-424.
61. Lian Z, Liu J, Pan J, Satiroglu Tufan NL, Zhu M, Arbuthnot P, et al. A cellular gene up-regulated by hepatitis B virus-encoded X antigen promotes hepatocellular growth and survival. Hepatology 2001;34:146-157.
62. Lian Z, Liu J, Wu M, Wang HY, Arbuthnot P, Kew M, et al. Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis. Hepatology 2007;45:1390-1399.
63. Yang WJ, Chang CJ, Yeh SH, Lin WH, Wang SH, Tsai TF, et al. Hepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3beta kinase pathways. Hepatology 2009;49:1515-1524.
64. Xu R, Zhang X, Zhang W, Fang Y, Zheng S, Yu XF. Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B x antigen mutants and hepatocellular carcinoma. Hepatology 2007;46:1810-1820.
65. Wang Y, Cui F, Lv Y, Li C, Xu X, Deng C, et al. HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004;39:318-324.
66. Tang H, Da L, Mao Y, Li Y, Li D, Xu Z, et al. Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology 2009;49:60-71.
67. Su JM, Lai XM, Lan KH, Li CP, Chao Y, Yen SH, et al. X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter. Hepatology 2007;46:402-413.
68. Na TY, Shin YK, Roh KJ, Kang SA, Hong I, Oh SJ, et al. Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2009;49:1122-1131.
69. Xu J, Yun X, Jiang J, Wei Y, Wu Y, Zhang W, et al. Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma via reducing Notchl cleavage. Hepatology 2010;52.
1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-1917.
2. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008;48:2047-2063.
3. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533-543.
4. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-156.
5. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-2576.
6. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981;2:1129-1133.
7. Di Bisceglie AM. Hepatitis B and hepatocellular carcinoma. Hepatology 2009;49:S56-60.
8. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582-592.
9. Sherlock S, Fox RA, Niazi SP, Scheuer PJ. Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1970;1:1243-1247.
10. Liu J, Fan D. Hepatitis B in China. Lancet 2007;369:1582-1583.
11. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004;350:1118-1129.
12. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-1257.
13. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis:from genes to environment. Nat Rev Cancer 2006;6:674-687.
14. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 2004;127:S56-61.
15. Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P. Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol 2000; 10:211-231.
16. Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virus-related hepatocellular carcinoma:paradigms for viral-related human carcinogenesis. Oncogene 2006;25:3823-3833.
17. Cougot D, Neuveut C, Buendia MA. HBV induced carcinogenesis. J Clin Virol 2005;34 Suppl 1:S75-78.
18. Neuveut C et al. Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol (2010),doi:10.1016/j.jhep.2009.10.033.
19. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003;22:5093-5107.
20. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-1745.
21. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004;78:12725-12734.
22. Su Q, Schroder CH, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P. Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas. Hepatology 1998;27:1109-1120.
23. Seto E, Mitchell PJ, Yen TS. Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 1990;344:72-74.
24. Maguire HF, Hoeffler JP, Siddiqui A. HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 1991;252:842-844.
25. Wu JY, Zhou ZY, Judd A, Cartwright CA, Robinson WS. The hepatitis B virus-encoded transcriptional trans-activator hbx appears to be a novel protein serine/threonine kinase. Cell 1990;63:687-695.
26. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991;351:317-320.
27. Bolos V, Grego-Bessa J, de la Pompa JL. Notch signaling in development and cancer. Endocr Rev 2007;28:339-363.
28. Bray SJ. Notch signalling:a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-689.
29. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995;268:225-232.
30. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling:cell fate control and signal integration in development. Science 1999;284:770-776.
31. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006;107:2223-2233.
32. Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, et al. Notchl Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression. J Biol Chem 2009;284:16183-16190.
33. Croquelois A, Blindenbacher A, Terracciano L, Wang X, Langer I, Radtke F, et al. Inducible inactivation of Notchl causes nodular regenerative hyperplasia in mice. Hepatology 2005;41:487-496.
34. Hubscher SG, Strain AJ. Another Notch to be added to the list of hepatocellular growth regulatory factors? Hepatology 2005;41:439-442.
35. Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notchl signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res 2003;63:8323-8329.
36. Kopan R, Ilagan MX. The canonical Notch signaling pathway:unfolding the activation mechanism. Cell 2009;137:216-233.
37. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature 2004;432:307-315.
38. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995;92:9363-9367.
39. Wei Y, Liu D, Zhou F, Ge Y, Xu J, Yun X, et al. Identification of beta-1,4-galactosyltransferase I as a target gene of HBx-induced cell cycle progression of hepatoma cell. J Hepatol 2008;49:1029-1037.
40. Radtke F, Raj K. The role of Notch in tumorigenesis:oncogene or tumour suppressor? Nat Rev Cancer 2003;3:756-767.
41. Maillard I, Pear WS. Notch and cancer:best to avoid the ups and downs. Cancer Cell 2003;3:203-205.
42. Zhang YW, Wang R, Liu Q, Zhang H, Liao FF, Xu H. Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci U S A 2007;104:10613-10618.
43. Selkoe D, Kopan R. Notch and Presenilin:regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 2003;26:565-597.
44. Haass C, De Strooper B. The presenilins in Alzheimer's disease-proteolysis holds the key. Science 1999;286:916-919.
45. Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, et al. Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase. J Biol Chem 2007;282:32264-32273.
46. Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, et al. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A 2001;98:10863-10868.
47. Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, et al. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell 2002; 110:751-762.
48. Cha MY, Kim CM, Park YM, Ryu WS. Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology 2004;39:1683-1693.
49. Sun BS, Zhu X, Clayton MM, Pan J, Feitelson MA. Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen. Hepatology 1998;27:228-239.
50. Kim H, Oh BK, Roncalli M, Park C, Yoon SM, Yoo JE, et al. Large liver cell change in hepatitis B virus-related liver cirrhosis. Hepatology 2009;50:752-762.
51. Dimri GP. What has senescence got to do with cancer? Cancer Cell 2005;7:505-512.
52. Mooi WJ, Peeper DS. Oncogene-induced cell senescence-halting on the road to cancer. N Engl J Med 2006;355:1037-1046.
53. Smith JR, Pereira-Smith OM. Replicative senescence:implications for in vivo aging and tumor suppression. Science 1996;273:63-67.
54. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001;11:S27-31.
55. Mathon NF, Lloyd AC. Cell senescence and cancer. Nat Rev Cancer 2001;1:203-213.
56. Schmitt CA. Senescence, apoptosis and therapy-cutting the lifelines of cancer. Nat Rev Cancer 2003;3:286-295.
57. Kahlem P, Dorken B, Schmitt CA. Cellular senescence in cancer treatment:friend or foe? J Clin Invest 2004; 113:169-174.
58. Campisi J. Senescent cells, tumor suppression, and organismal aging:good citizens, bad neighbors. Cell 2005; 120:513-522.
59. Braig M, Schmitt CA. Oncogene-induced senescence:putting the brakes on tumor development. Cancer Res 2006;66:2881-2884.
60. Campisi J, d'Adda di Fagagna F. Cellular senescence:when bad things happen to good cells. Nat Rev Mol Cell Biol 2007;8:729-740.
61. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell 2007;130:223-233.
62. Hemann MT, Narita M. Oncogenes and senescence:breaking down in the fast lane. Genes Dev 2007;21:1-5.
63. Yaswen P, Campisi J. Oncogene-induced senescence pathways weave an intricate tapestry. Cell 2007;128:233-234.
64. Prieur A, Peeper DS. Cellular senescence in vivo:a barrier to tumorigenesis. Curr Opin Cell Biol 2008;20:150-155.
1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533-543.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-156.
3. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-2576.
4. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-1917.
5. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008;48:2047-2063.
6. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981;2:1129-1133.
7. Di Bisceglie AM. Hepatitis B and hepatocellular carcinoma. Hepatology 2009;49:S56-60.
8. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582-592.
9. Sherlock S, Fox RA, Niazi SP, Scheuer PJ. Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1970;1:1243-1247.
10. Liu J, Fan D. Hepatitis B in China. Lancet 2007;369:1582-1583.
11. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004;350:1118-1129.
12. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-1257.
13. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis:from genes to environment. Nat Rev Cancer 2006;6:674-687.
14. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519-524.
15. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003;9:416-423.
16. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004;78:12725-12734.
17. Cromlish JA. Hepatitis B virus-induced hepatocellular carcinoma:possible roles for HBx. Trends Microbiol 1996;4:270-274.
18. Butel JS, Lee TH, Slagle BL. Is the DNA repair system involved in hepatitis-B-virus-mediated hepatocellular carcinogenesis? Trends Microbiol 1996;4:119-124.
19. Mosialos G. The role of Rel/NF-kappa B proteins in viral oncogenesis and the regulation of viral transcription. Semin Cancer Biol 1997;8:121-129.
20. Singh M, Kumar V. Transgenic mouse models of hepatitis B virus-associated hepatocellular carcinoma. Rev Med Virol 2003;13:243-253.
21. Kim CM, Koike K, Saito I, Miyamura T, Jay G HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991;351:317-320.
22. Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 1993;361:742-745.
23. Will H. The X-protein of hepatitis B virus. Facts and fiction. J Hepatol 1991;13 Suppl 4:S56-57.
24. Kew MC. Increasing evidence that hepatitis B virus X gene protein and p53 protein may interact in the pathogenesis of hepatocellular carcinoma. Hepatology 1997;25:1037-1038.
25. Branda M, Wands JR. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology 2006;43:891-902.
26. Diao J, Garces R, Richardson CD. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 2001;12:189-205.
27. Feitelson MA, Duan LX. Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol 1997;150:1141-1157.
28. Wei Y, Liu D, Zhou F, Ge Y, Xu J, Yun X, et al. Identification of beta-1,4-galactosyltransferase I as a target gene of HBx-induced cell cycle progression of hepatoma cell. J Hepatol 2008;49:1029-1037.
29. Xu J, Yun X, Jiang J, Wei Y, Wu Y, Zhang W, et al. Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma via reducing Notchl cleavage. Hepatology 2010;52.
30. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions:the importance of changing cell state in development and disease. J Clin Invest 2009;119:1438-1449.
31. Kalluri R. EMT:when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009;119:1417-1419.
32. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420-1428.
33. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009;119:1429-1437.
34. Arias AM. Epithelial mesenchymal interactions in cancer and development. Cell 2001; 105:425-431.
35. Kang Y, Massague J. Epithelial-mesenchymal transitions:twist in development and metastasis. Cell 2004; 118:277-279.
36. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139:871-890.
37. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740-746.
38. Moreno-Bueno G, Peinado H, Molina P, Olmeda D, Cubillo E, Santos V, et al. The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat Protoc 2009;4:1591-1613.
39. Prindull G, Zipori D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 2004; 103:2892-2899.
40. Revenu C, Gilmour D. EMT 2.0:shaping epithelia through collective migration. Curr Opin Genet Dev 2009; 19:338-342.
41. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:548-558.
42. Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology 2009;50:1464-1474.
43. Yang J, Weinberg RA. Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis. Dev Cell 2008;14:818-829.
44. Choi SS, Diehl AM. Epithelial-to-mesenchymal transitions in the liver. Hepatology 2009;50:2007-2013.
45. Hay ED. An overview of epithelio-mesenchymal transformation. Acta. Anat. (Basel) 1995; 154:8-20.
46. Moreno-Bueno G, Peinado H, Molina P, Olmeda D, Cubillo E, Santos V, et al. The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat. Protocols 2009;4:1591-1613.
47. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell Biol. 2005;17:548-558.
48. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol.2006;7:131-142.
49. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002;2:442-454.
50. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression:an alliance against the epithelial phenotype? Nat. Rev. Cancer 2007;7:415-428.
51. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival:implications in development and cancer. Development 2005;132:3151-3161.
52. Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 2008;27:6958-6969.
53. Moreno-Bueno G. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res.2006;66:9543-9556.
54. De Craene B. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res. 2005;65:6237-6244.
55. Boyer B, Tucker GC, Valles AM, Franke WW, Thiery JP. Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells. J Cell Biol 1989;109:1495-1509.
56. Chen L, Chan THM, Yuan Y-F, Hu L, Huang J, Ma S, et al. CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients. The Journal of Clinical Investigation 2010;0:0-0.
57. Tang DJ, Dong SS, Ma NF, Xie D, Chen L, Fu L, et al. Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma. Hepatology 2009.
58. Sun T, Zhao N, Zhao XL, Gu Q, Zhang SW, Che N, et al. Expression and functional significance of Twistl in hepatocellular carcinoma:its role in vasculogenic mimicry. Hepatology 2010;51:545-556.
59. van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, et al. Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol 2009;5:1169-1179.
60. Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res 2008;68:2391-2399.
61. Lee TK, Man K, Poon RT, Lo CM, Yuen AP, Ng IO, et al. Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition. Cancer Res 2006;66:9948-9956.
62. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. Laminin-5 with transforming growth factor-betal induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 2005;129:1375-1383.
63. Lee YI, Kang-Park S, Do SI. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem 2001;276:16969-16977.
64. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 2005;19:159-170.
65. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3 beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004;6:931-940.
1. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling:cell fate control and signal integration in development. Science 1999;284:770-776.
2. Morgan TH. The theory of the gene. Am. Nat.1917;51:513-544.
3. Bolos V, Grego-Bessa J, de la Pompa JL. Notch signaling in development and cancer. Endocr Rev 2007;28:339-363.
4. Tien AC, Rajan A, Bellen HJ. A Notch updated. J Cell Biol 2009; 184:621-629.
5. Roy M, Pear WS, Aster JC. The multifaceted role of Notch in cancer. Curr Opin Genet Dev 2007;17:52-59.
6. Radtke F, Raj K. The role of Notch in tumorigenesis:oncogene or tumour suppressor? Nat Rev Cancer 2003;3:756-767.
7. Maillard I, Pear WS. Notch and cancer:best to avoid the ups and downs. Cancer Cell 2003;3:203-205.
8. Wharton KA. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 1985;43:567-581.
9. Kidd S, Kelley MR, Young MW. Sequence of the notch locus of Drosophila melanogaster:relationship of the encoded protein to mammalian clotting and growth factors. Mol. Cell Biol.1986;6:3094-3108.
10. del Amo FF. Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch. Genomics 1993; 15:259-264.
11. Bray SJ. Notch signalling:a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-689.
12. Weinmaster G, Roberts VJ, Lemke G. Notch2:a second mammalian Notch gene. Development 1992;116:931-941.
13. Lardelli M, Lendahl U. Motch A and motch B:two mouse Notch homologues coexpressed in a wide variety of tissues. Exp. Cell Res.1993;204:364-372.
14. Lardelli M, Dahlstrand J, Lendahl U. The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech. Dev.1994;46:123-136.
15. Uyttendaele H. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development 1996; 122:2251-2259.
16. Haines N, Irvine KD. Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 2003;4:786-797.
17. Kimble J, Simpson P. The LIN-12/Notch signaling pathway and its regulation. Annu Rev Cell Dev Biol 1997;13:333-361.
18. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995;268:225-232.
19. Kopan R, Ilagan MX. The canonical Notch signaling pathway:unfolding the activation mechanism. Cell 2009;137:216-233.
20. Weinmaster G. Notch signal transduction:a real rip and more. Curr Opin Genet Dev 2000; 10:363-369.
21. Fortini ME. Notch signaling:the core pathway and its posttranslational regulation. Dev Cell 2009; 16:633-647.
22. Hansson EM, Lendahl U, Chapman G. Notch signaling in development and disease. Semin Cancer Biol 2004;14:320-328.
23. Lewis J. Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 1998;9:583-589.
24. Jones P, May G, Healy L, Brown J, Hoyne G, Delassus S, et al. Stromal expression of Jagged 1 promotes colony formation by fetal hematopoietic progenitor cells. Blood 1998;92:1505-1511.
25. Robey E. Regulation of T cell fate by Notch. Annu Rev Immunol 1999;17:283-295.
26. Radtke F, Wilson A, MacDonald HR. Notch signaling in T-and B-cell development. Curr Opin Immunol 2004; 16:174-179.
27. Pourquie O. Skin development:delta laid bare. Curr Biol 2000;10:R425-428.
28. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 2001;20:3427-3436.
29. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006; 107:2223-2233.
30. Reynolds TC, Smith SD, Sklar J. Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the beta T cell receptor gene in human lymphoblastic neoplasms. Cell 1987;50:107-117.
31. Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996; 183:2283-2291.
32. Pui JC, Allman D, Xu L, DeRocco S, Karnell FG, Bakkour S, et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 1999; 11:299-308.
33. Girard L, Hanna Z, Beaulieu N, Hoemann CD, Simard C, Kozak CA, et al. Frequent provirus insertional mutagenesis of Notchl in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notchl for oncogenesis. Genes Dev 1996;10:1930-1944.
34. Rohn JL, Lauring AS, Linenberger ML, Overbaugh J. Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. J Virol 1996;70:8071-8080.
35. Yan XQ, Sarmiento U, Sun Y, Huang G, Guo J, Juan T, et al. A novel Notch ligand, D114, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Blood 2001;98:3793-3799.
36. Dorsch M, Zheng G, Yowe D, Rao P, Wang Y, Shen Q, et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood 2002; 100:2046-2055.
37. Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003;23:655-664.
38. Callahan R, Smith GH. MMTV-induced mammary tumorigenesis:gene discovery, progression to malignancy and cellular pathways. Oncogene 2000;19:992-1001.
39. Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino G, et al. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev 1992;6:345-355.
40. Dievart A, Beaulieu N, Jolicoeur P. Involvement of Notchl in the development of mouse mammary tumors. Oncogene 1999; 18:5973-5981.
41. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 2002;8:979-986.
42. Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci U S A 1995;92:6414-6418.
43. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol 2004;14:341-347.
44. Dotto GP. Notch tumor suppressor function. Oncogene 2008;27:5115-5123.
45. Fuchs E, Raghavan S. Getting under the skin of epidermal morphogenesis. Nat Rev Genet 2002;3:199-209.
46. Lefort K, Dotto GP. Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol 2004;14:374-386.
47. Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ 2002;9:842-855.
48. Talora C, Sgroi DC, Crum CP, Dotto GP. Specific down-modulation of Notchl signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev 2002;16:2252-2263.
49. Chu J, Jeffries S, Norton JE, Capobianco AJ, Bresnick EH. Repression of activator protein-1-mediated transcriptional activation by the Notch-1 intracellular domain. J Biol Chem 2002;277:7587-7597.
50. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notchl functions as a tumor suppressor in mouse skin. Nat Genet 2003;33:416-421.
51. Thelu J, Rossio P, Favier B. Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol 2002;2:7.
52. Collins BJ, Kleeberger W, Ball DW. Notch in lung development and lung cancer. Semin Cancer Biol 2004; 14:357-364.
53. Kohler C, Bell AW, Bowen WC, Monga SP, Fleig W, Michalopoulos GK. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration. Hepatology 2004;39:1056-1065.
54. Croquelois A, Blindenbacher A, Terracciano L, Wang X, Langer I, Radtke F, et al. Inducible inactivation of Notchl causes nodular regenerative hyperplasia in mice. Hepatology 2005;41:487-496.
55. Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notchl signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res 2003;63:8323-8329.
56. Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, et al. Notchl Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression. J Biol Chem 2009;284:16183-16190.
57. Maliekal TT, Bajaj J, Giri V, Subramanyam D, Krishna S. The role of Notch signaling in human cervical cancer:implications for solid tumors. Oncogene 2008;27:5110-5114.
58. Parr C, Watkins G, Jiang WG. The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med 2004; 14:779-786.
59. Cavin LG, Venkatraman M, Factor VM, Kaur S, Schroeder I, Mercurio F, et al. Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis. Cancer Res 2004;64:7030-7038.
60. Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res 2001;61:3200-3205.
61. Sarmento LM, Huang H, Limon A, Gordon W, Fernandes J, Tavares MJ, et al. Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kip1 degradation. J Exp Med 2005;202:157-168.
62. Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene 2005;24:6333-6344.
63. Maillard I, Fang T, Pear WS. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol 2005;23:945-974.
64. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 2002;25:471-490.
65. Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 2005;8:13-23.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-156.
3. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-1917.
4. Bruix J, Boix L, Sala M, Llovet JM. Focus on hepatocellular carcinoma. Cancer Cell 2004;5:215-219.
5. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-2576.
6. Boyle P, Levin B. World Cancer Report 2008. Lyon:International Agency for Research on Cancer (IARC),2008.
7. Cancer incidence in five continents. Volume Ⅷ. IARC Sci Publ 2002:1-781.
8. Colombo M, Sangiovanni A. Etiology, natural history and treatment of hepatocellular carcinoma. Antiviral Res 2003;60:145-150.
9. Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 2005;9:191-211, v.
10. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis:from genes to environment. Nat Rev Cancer 2006;6:674-687.
11. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31:339-346.
12. Badvie S. Hepatocellular carcinoma. Postgrad Med J 2000;76:4-11.
13. Limdi JK, Crampton JR. Hereditary haemochromatosis. QJM 2004;97:315-324.
14. Sarkany RP. The management of porphyria cutanea tarda. Clin Exp Dermatol 2001;26:225-232.
15. Parfrey H, Mahadeva R, Lomas DA. Alpha(1)-antitrypsin deficiency, liver disease and emphysema. Int J Biochem Cell Biol 2003;35:1009-1014.
16. Tanguay RM, Jorquera R, Poudrier J, St-Louis M. Tyrosine and its catabolites: from disease to cancer. Acta Biochim Pol 1996;43:209-216.
17. El-Serag HB, Tran T, Everhart JE. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004; 126:460-468.
18. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis. Hepatology 2006;43:S99-S112.
19. Adams LA, Angulo P. Recent concepts in non-alcoholic fatty liver disease. Diabet Med 2005;22:1129-1133.
20. Bosch FX, Ribes J, Borras J. Epidemiology of primary liver cancer. Semin Liver Dis 1999;19:271-285.
21. Liaw YF, Tai DI, Chu CM, Lin DY, Sheen IS, Chen TJ, et al. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis. A prospective study. Gastroenterology 1986;90:263-267.
22. Sun Z, Lu P, Gail MH, Pee D, Zhang Q, Ming L, et al. Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 1999;30:379-383.
23. Bruno S, Silini E, Crosignani A, Borzio F, Leandro G, Bono F, et al. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis:a prospective study. Hepatology 1997;25:754-758.
24. Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Tapias JM, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;2:1004-1006.
25. Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med 1991;325:675-680.
26. Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797-1801.
27. Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985;313:1256-1262.
28. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582-592.
29. Sherlock S, Fox RA, Niazi SP, Scheuer PJ. Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1970;1:1243-1247.
30. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004;350:1118-1129.
31. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-1257.
32. Liu J, Fan D. Hepatitis B in China. Lancet 2007;369:1582-1583.
33. Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000;64:51-68.
34. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-1745.
35. Lau JY, Wright TL. Molecular virology and pathogenesis of hepatitis B. Lancet 1993;342:1335-1340.
36. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 2004;127:S56-61.
37. Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P. Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol 2000; 10:211-231.
38. Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virus-related hepatocellular carcinoma:paradigms for viral-related human carcinogenesis. Oncogene 2006;25:3823-3833.
39. Cougot D, Neuveut C, Buendia MA. HBV induced carcinogenesis. J Clin Virol 2005;34 Suppl 1:S75-78.
40. Christine N, Yu W, Marie Annick B. Mechanisms of HBV-related hepatocarcinogenesis. Journal of hepatology.
41. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003;22:5093-5107.
42. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004;78:12725-12734.
43. Diao J, Garces R, Richardson CD. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 2001; 12:189-205.
44. Butel JS, Lee TH, Slagle BL. Is the DNA repair system involved in hepatitis-B-virus-mediated hepatocellular carcinogenesis? Trends Microbiol 1996;4:119-124.
45. Cromlish JA. Hepatitis B virus-induced hepatocellular carcinoma:possible roles for HBx. Trends Microbiol 1996;4:270-274.
46. Feitelson MA, Duan LX. Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol 1997;150:1141-1157.
47. Su Q, Schroder CH, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P. Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas. Hepatology 1998;27:1109-1120.
48. Haruna Y, Hayashi N, Katayama K, Yuki N, Kasahara A, Sasaki Y, et al. Expression of X protein and hepatitis B virus replication in chronic hepatitis. Hepatology 1991;13:417-421.
49. Vitvitski-Trepo L, Kay A, Pichoud C, Chevallier P, de Dinechin S, Shamoon BM, et al. Early and frequent detection of HBxAg and/or anti-HBx in hepatitis B virus infection. Hepatology 1990;12:1278-1283.
50. Wang WL, London WT, Lega L, Feitelson MA. HBxAg in the liver from carrier patients with chronic hepatitis and cirrhosis. Hepatology 1991;14:29-37.
51. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991;351:317-320.
52. Zheng Y, Chen WL, Louie SG, Yen TS, Ou JH. Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 2007;45:16-21.
53. Seto E, Mitchell PJ, Yen TS. Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 1990;344:72-74.
54. Maguire HF, Hoeffler JP, Siddiqui A. HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 1991;252:842-844.
55. Wu JY, Zhou ZY, Judd A, Cartwright CA, Robinson WS. The hepatitis B virus-encoded transcriptional trans-activator hbx appears to be a novel protein serine/threonine kinase. Cell 1990;63:687-695.
56. Cha MY, Kim CM, Park YM, Ryu WS. Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology 2004;39:1683-1693.
57. Kew MC. Increasing evidence that hepatitis B virus X gene protein and p53 protein may interact in the pathogenesis of hepatocellular carcinoma. Hepatology 1997;25:1037-1038.
58. Kong HJ, Park MJ, Hong S, Yu HJ, Lee YC, Choi YH, et al. Hepatitis B virus X protein regulates transactivation activity and protein stability of the cancer-amplified transcription coactivator ASC-2. Hepatology 2003;38:1258-1266.
59. Lara-Pezzi E, Majano PL, Gomez-Gonzalo M, Garcia-Monzon C, Moreno-Otero R, Levrero M, et al. The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes. Hepatology 1998;28:1013-1021.
60. Lian Z, Liu J, Li L, Li X, Clayton M, Wu MC, et al. Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of beta-catenin. Hepatology 2006;43:415-424.
61. Lian Z, Liu J, Pan J, Satiroglu Tufan NL, Zhu M, Arbuthnot P, et al. A cellular gene up-regulated by hepatitis B virus-encoded X antigen promotes hepatocellular growth and survival. Hepatology 2001;34:146-157.
62. Lian Z, Liu J, Wu M, Wang HY, Arbuthnot P, Kew M, et al. Hepatitis B x antigen up-regulates vascular endothelial growth factor receptor 3 in hepatocarcinogenesis. Hepatology 2007;45:1390-1399.
63. Yang WJ, Chang CJ, Yeh SH, Lin WH, Wang SH, Tsai TF, et al. Hepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3beta kinase pathways. Hepatology 2009;49:1515-1524.
64. Xu R, Zhang X, Zhang W, Fang Y, Zheng S, Yu XF. Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B x antigen mutants and hepatocellular carcinoma. Hepatology 2007;46:1810-1820.
65. Wang Y, Cui F, Lv Y, Li C, Xu X, Deng C, et al. HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology 2004;39:318-324.
66. Tang H, Da L, Mao Y, Li Y, Li D, Xu Z, et al. Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology 2009;49:60-71.
67. Su JM, Lai XM, Lan KH, Li CP, Chao Y, Yen SH, et al. X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter. Hepatology 2007;46:402-413.
68. Na TY, Shin YK, Roh KJ, Kang SA, Hong I, Oh SJ, et al. Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma. Hepatology 2009;49:1122-1131.
69. Xu J, Yun X, Jiang J, Wei Y, Wu Y, Zhang W, et al. Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma via reducing Notchl cleavage. Hepatology 2010;52.
1. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-1917.
2. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008;48:2047-2063.
3. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533-543.
4. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-156.
5. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-2576.
6. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981;2:1129-1133.
7. Di Bisceglie AM. Hepatitis B and hepatocellular carcinoma. Hepatology 2009;49:S56-60.
8. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582-592.
9. Sherlock S, Fox RA, Niazi SP, Scheuer PJ. Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1970;1:1243-1247.
10. Liu J, Fan D. Hepatitis B in China. Lancet 2007;369:1582-1583.
11. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004;350:1118-1129.
12. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-1257.
13. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis:from genes to environment. Nat Rev Cancer 2006;6:674-687.
14. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 2004;127:S56-61.
15. Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P. Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol 2000; 10:211-231.
16. Kremsdorf D, Soussan P, Paterlini-Brechot P, Brechot C. Hepatitis B virus-related hepatocellular carcinoma:paradigms for viral-related human carcinogenesis. Oncogene 2006;25:3823-3833.
17. Cougot D, Neuveut C, Buendia MA. HBV induced carcinogenesis. J Clin Virol 2005;34 Suppl 1:S75-78.
18. Neuveut C et al. Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol (2010),doi:10.1016/j.jhep.2009.10.033.
19. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003;22:5093-5107.
20. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337:1733-1745.
21. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004;78:12725-12734.
22. Su Q, Schroder CH, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P. Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas. Hepatology 1998;27:1109-1120.
23. Seto E, Mitchell PJ, Yen TS. Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 1990;344:72-74.
24. Maguire HF, Hoeffler JP, Siddiqui A. HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 1991;252:842-844.
25. Wu JY, Zhou ZY, Judd A, Cartwright CA, Robinson WS. The hepatitis B virus-encoded transcriptional trans-activator hbx appears to be a novel protein serine/threonine kinase. Cell 1990;63:687-695.
26. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991;351:317-320.
27. Bolos V, Grego-Bessa J, de la Pompa JL. Notch signaling in development and cancer. Endocr Rev 2007;28:339-363.
28. Bray SJ. Notch signalling:a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-689.
29. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995;268:225-232.
30. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling:cell fate control and signal integration in development. Science 1999;284:770-776.
31. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006;107:2223-2233.
32. Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, et al. Notchl Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression. J Biol Chem 2009;284:16183-16190.
33. Croquelois A, Blindenbacher A, Terracciano L, Wang X, Langer I, Radtke F, et al. Inducible inactivation of Notchl causes nodular regenerative hyperplasia in mice. Hepatology 2005;41:487-496.
34. Hubscher SG, Strain AJ. Another Notch to be added to the list of hepatocellular growth regulatory factors? Hepatology 2005;41:439-442.
35. Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notchl signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res 2003;63:8323-8329.
36. Kopan R, Ilagan MX. The canonical Notch signaling pathway:unfolding the activation mechanism. Cell 2009;137:216-233.
37. Lowe SW, Cepero E, Evan G. Intrinsic tumour suppression. Nature 2004;432:307-315.
38. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 1995;92:9363-9367.
39. Wei Y, Liu D, Zhou F, Ge Y, Xu J, Yun X, et al. Identification of beta-1,4-galactosyltransferase I as a target gene of HBx-induced cell cycle progression of hepatoma cell. J Hepatol 2008;49:1029-1037.
40. Radtke F, Raj K. The role of Notch in tumorigenesis:oncogene or tumour suppressor? Nat Rev Cancer 2003;3:756-767.
41. Maillard I, Pear WS. Notch and cancer:best to avoid the ups and downs. Cancer Cell 2003;3:203-205.
42. Zhang YW, Wang R, Liu Q, Zhang H, Liao FF, Xu H. Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci U S A 2007;104:10613-10618.
43. Selkoe D, Kopan R. Notch and Presenilin:regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 2003;26:565-597.
44. Haass C, De Strooper B. The presenilins in Alzheimer's disease-proteolysis holds the key. Science 1999;286:916-919.
45. Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, et al. Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase. J Biol Chem 2007;282:32264-32273.
46. Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, et al. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A 2001;98:10863-10868.
47. Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, et al. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell 2002; 110:751-762.
48. Cha MY, Kim CM, Park YM, Ryu WS. Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology 2004;39:1683-1693.
49. Sun BS, Zhu X, Clayton MM, Pan J, Feitelson MA. Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen. Hepatology 1998;27:228-239.
50. Kim H, Oh BK, Roncalli M, Park C, Yoon SM, Yoo JE, et al. Large liver cell change in hepatitis B virus-related liver cirrhosis. Hepatology 2009;50:752-762.
51. Dimri GP. What has senescence got to do with cancer? Cancer Cell 2005;7:505-512.
52. Mooi WJ, Peeper DS. Oncogene-induced cell senescence-halting on the road to cancer. N Engl J Med 2006;355:1037-1046.
53. Smith JR, Pereira-Smith OM. Replicative senescence:implications for in vivo aging and tumor suppression. Science 1996;273:63-67.
54. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 2001;11:S27-31.
55. Mathon NF, Lloyd AC. Cell senescence and cancer. Nat Rev Cancer 2001;1:203-213.
56. Schmitt CA. Senescence, apoptosis and therapy-cutting the lifelines of cancer. Nat Rev Cancer 2003;3:286-295.
57. Kahlem P, Dorken B, Schmitt CA. Cellular senescence in cancer treatment:friend or foe? J Clin Invest 2004; 113:169-174.
58. Campisi J. Senescent cells, tumor suppression, and organismal aging:good citizens, bad neighbors. Cell 2005; 120:513-522.
59. Braig M, Schmitt CA. Oncogene-induced senescence:putting the brakes on tumor development. Cancer Res 2006;66:2881-2884.
60. Campisi J, d'Adda di Fagagna F. Cellular senescence:when bad things happen to good cells. Nat Rev Mol Cell Biol 2007;8:729-740.
61. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell 2007;130:223-233.
62. Hemann MT, Narita M. Oncogenes and senescence:breaking down in the fast lane. Genes Dev 2007;21:1-5.
63. Yaswen P, Campisi J. Oncogene-induced senescence pathways weave an intricate tapestry. Cell 2007;128:233-234.
64. Prieur A, Peeper DS. Cellular senescence in vivo:a barrier to tumorigenesis. Curr Opin Cell Biol 2008;20:150-155.
1. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2:533-543.
2. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153-156.
3. El-Serag HB, Rudolph KL. Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 2007; 132:2557-2576.
4. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907-1917.
5. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008;48:2047-2063.
6. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981;2:1129-1133.
7. Di Bisceglie AM. Hepatitis B and hepatocellular carcinoma. Hepatology 2009;49:S56-60.
8. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet 2009;373:582-592.
9. Sherlock S, Fox RA, Niazi SP, Scheuer PJ. Chronic liver disease and primary liver-cell cancer with hepatitis-associated (Australia) antigen in serum. Lancet 1970;1:1243-1247.
10. Liu J, Fan D. Hepatitis B in China. Lancet 2007;369:1582-1583.
11. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med 2004;350:1118-1129.
12. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-1257.
13. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis:from genes to environment. Nat Rev Cancer 2006;6:674-687.
14. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002;35:519-524.
15. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003;9:416-423.
16. Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004;78:12725-12734.
17. Cromlish JA. Hepatitis B virus-induced hepatocellular carcinoma:possible roles for HBx. Trends Microbiol 1996;4:270-274.
18. Butel JS, Lee TH, Slagle BL. Is the DNA repair system involved in hepatitis-B-virus-mediated hepatocellular carcinogenesis? Trends Microbiol 1996;4:119-124.
19. Mosialos G. The role of Rel/NF-kappa B proteins in viral oncogenesis and the regulation of viral transcription. Semin Cancer Biol 1997;8:121-129.
20. Singh M, Kumar V. Transgenic mouse models of hepatitis B virus-associated hepatocellular carcinoma. Rev Med Virol 2003;13:243-253.
21. Kim CM, Koike K, Saito I, Miyamura T, Jay G HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 1991;351:317-320.
22. Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 1993;361:742-745.
23. Will H. The X-protein of hepatitis B virus. Facts and fiction. J Hepatol 1991;13 Suppl 4:S56-57.
24. Kew MC. Increasing evidence that hepatitis B virus X gene protein and p53 protein may interact in the pathogenesis of hepatocellular carcinoma. Hepatology 1997;25:1037-1038.
25. Branda M, Wands JR. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology 2006;43:891-902.
26. Diao J, Garces R, Richardson CD. X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. Cytokine Growth Factor Rev 2001;12:189-205.
27. Feitelson MA, Duan LX. Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol 1997;150:1141-1157.
28. Wei Y, Liu D, Zhou F, Ge Y, Xu J, Yun X, et al. Identification of beta-1,4-galactosyltransferase I as a target gene of HBx-induced cell cycle progression of hepatoma cell. J Hepatol 2008;49:1029-1037.
29. Xu J, Yun X, Jiang J, Wei Y, Wu Y, Zhang W, et al. Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma via reducing Notchl cleavage. Hepatology 2010;52.
30. Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions:the importance of changing cell state in development and disease. J Clin Invest 2009;119:1438-1449.
31. Kalluri R. EMT:when epithelial cells decide to become mesenchymal-like cells. J Clin Invest 2009;119:1417-1419.
32. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009;119:1420-1428.
33. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009;119:1429-1437.
34. Arias AM. Epithelial mesenchymal interactions in cancer and development. Cell 2001; 105:425-431.
35. Kang Y, Massague J. Epithelial-mesenchymal transitions:twist in development and metastasis. Cell 2004; 118:277-279.
36. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009; 139:871-890.
37. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740-746.
38. Moreno-Bueno G, Peinado H, Molina P, Olmeda D, Cubillo E, Santos V, et al. The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat Protoc 2009;4:1591-1613.
39. Prindull G, Zipori D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 2004; 103:2892-2899.
40. Revenu C, Gilmour D. EMT 2.0:shaping epithelia through collective migration. Curr Opin Genet Dev 2009; 19:338-342.
41. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:548-558.
42. Yang MH, Chen CL, Chau GY, Chiou SH, Su CW, Chou TY, et al. Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma. Hepatology 2009;50:1464-1474.
43. Yang J, Weinberg RA. Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis. Dev Cell 2008;14:818-829.
44. Choi SS, Diehl AM. Epithelial-to-mesenchymal transitions in the liver. Hepatology 2009;50:2007-2013.
45. Hay ED. An overview of epithelio-mesenchymal transformation. Acta. Anat. (Basel) 1995; 154:8-20.
46. Moreno-Bueno G, Peinado H, Molina P, Olmeda D, Cubillo E, Santos V, et al. The morphological and molecular features of the epithelial-to-mesenchymal transition. Nat. Protocols 2009;4:1591-1613.
47. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell Biol. 2005;17:548-558.
48. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol.2006;7:131-142.
49. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002;2:442-454.
50. Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression:an alliance against the epithelial phenotype? Nat. Rev. Cancer 2007;7:415-428.
51. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival:implications in development and cancer. Development 2005;132:3151-3161.
52. Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 2008;27:6958-6969.
53. Moreno-Bueno G. Genetic profiling of epithelial cells expressing E-cadherin repressors reveals a distinct role for Snail, Slug, and E47 factors in epithelial-mesenchymal transition. Cancer Res.2006;66:9543-9556.
54. De Craene B. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res. 2005;65:6237-6244.
55. Boyer B, Tucker GC, Valles AM, Franke WW, Thiery JP. Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells. J Cell Biol 1989;109:1495-1509.
56. Chen L, Chan THM, Yuan Y-F, Hu L, Huang J, Ma S, et al. CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients. The Journal of Clinical Investigation 2010;0:0-0.
57. Tang DJ, Dong SS, Ma NF, Xie D, Chen L, Fu L, et al. Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma. Hepatology 2009.
58. Sun T, Zhao N, Zhao XL, Gu Q, Zhang SW, Che N, et al. Expression and functional significance of Twistl in hepatocellular carcinoma:its role in vasculogenic mimicry. Hepatology 2010;51:545-556.
59. van Zijl F, Zulehner G, Petz M, Schneller D, Kornauth C, Hau M, et al. Epithelial-mesenchymal transition in hepatocellular carcinoma. Future Oncol 2009;5:1169-1179.
60. Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res 2008;68:2391-2399.
61. Lee TK, Man K, Poon RT, Lo CM, Yuen AP, Ng IO, et al. Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition. Cancer Res 2006;66:9948-9956.
62. Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S. Laminin-5 with transforming growth factor-betal induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 2005;129:1375-1383.
63. Lee YI, Kang-Park S, Do SI. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem 2001;276:16969-16977.
64. Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J, et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 2005;19:159-170.
65. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3 beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004;6:931-940.
1. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling:cell fate control and signal integration in development. Science 1999;284:770-776.
2. Morgan TH. The theory of the gene. Am. Nat.1917;51:513-544.
3. Bolos V, Grego-Bessa J, de la Pompa JL. Notch signaling in development and cancer. Endocr Rev 2007;28:339-363.
4. Tien AC, Rajan A, Bellen HJ. A Notch updated. J Cell Biol 2009; 184:621-629.
5. Roy M, Pear WS, Aster JC. The multifaceted role of Notch in cancer. Curr Opin Genet Dev 2007;17:52-59.
6. Radtke F, Raj K. The role of Notch in tumorigenesis:oncogene or tumour suppressor? Nat Rev Cancer 2003;3:756-767.
7. Maillard I, Pear WS. Notch and cancer:best to avoid the ups and downs. Cancer Cell 2003;3:203-205.
8. Wharton KA. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 1985;43:567-581.
9. Kidd S, Kelley MR, Young MW. Sequence of the notch locus of Drosophila melanogaster:relationship of the encoded protein to mammalian clotting and growth factors. Mol. Cell Biol.1986;6:3094-3108.
10. del Amo FF. Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch. Genomics 1993; 15:259-264.
11. Bray SJ. Notch signalling:a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-689.
12. Weinmaster G, Roberts VJ, Lemke G. Notch2:a second mammalian Notch gene. Development 1992;116:931-941.
13. Lardelli M, Lendahl U. Motch A and motch B:two mouse Notch homologues coexpressed in a wide variety of tissues. Exp. Cell Res.1993;204:364-372.
14. Lardelli M, Dahlstrand J, Lendahl U. The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech. Dev.1994;46:123-136.
15. Uyttendaele H. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development 1996; 122:2251-2259.
16. Haines N, Irvine KD. Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 2003;4:786-797.
17. Kimble J, Simpson P. The LIN-12/Notch signaling pathway and its regulation. Annu Rev Cell Dev Biol 1997;13:333-361.
18. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995;268:225-232.
19. Kopan R, Ilagan MX. The canonical Notch signaling pathway:unfolding the activation mechanism. Cell 2009;137:216-233.
20. Weinmaster G. Notch signal transduction:a real rip and more. Curr Opin Genet Dev 2000; 10:363-369.
21. Fortini ME. Notch signaling:the core pathway and its posttranslational regulation. Dev Cell 2009; 16:633-647.
22. Hansson EM, Lendahl U, Chapman G. Notch signaling in development and disease. Semin Cancer Biol 2004;14:320-328.
23. Lewis J. Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol 1998;9:583-589.
24. Jones P, May G, Healy L, Brown J, Hoyne G, Delassus S, et al. Stromal expression of Jagged 1 promotes colony formation by fetal hematopoietic progenitor cells. Blood 1998;92:1505-1511.
25. Robey E. Regulation of T cell fate by Notch. Annu Rev Immunol 1999;17:283-295.
26. Radtke F, Wilson A, MacDonald HR. Notch signaling in T-and B-cell development. Curr Opin Immunol 2004; 16:174-179.
27. Pourquie O. Skin development:delta laid bare. Curr Biol 2000;10:R425-428.
28. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 2001;20:3427-3436.
29. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006; 107:2223-2233.
30. Reynolds TC, Smith SD, Sklar J. Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the beta T cell receptor gene in human lymphoblastic neoplasms. Cell 1987;50:107-117.
31. Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996; 183:2283-2291.
32. Pui JC, Allman D, Xu L, DeRocco S, Karnell FG, Bakkour S, et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 1999; 11:299-308.
33. Girard L, Hanna Z, Beaulieu N, Hoemann CD, Simard C, Kozak CA, et al. Frequent provirus insertional mutagenesis of Notchl in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notchl for oncogenesis. Genes Dev 1996;10:1930-1944.
34. Rohn JL, Lauring AS, Linenberger ML, Overbaugh J. Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. J Virol 1996;70:8071-8080.
35. Yan XQ, Sarmiento U, Sun Y, Huang G, Guo J, Juan T, et al. A novel Notch ligand, D114, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Blood 2001;98:3793-3799.
36. Dorsch M, Zheng G, Yowe D, Rao P, Wang Y, Shen Q, et al. Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. Blood 2002; 100:2046-2055.
37. Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003;23:655-664.
38. Callahan R, Smith GH. MMTV-induced mammary tumorigenesis:gene discovery, progression to malignancy and cellular pathways. Oncogene 2000;19:992-1001.
39. Jhappan C, Gallahan D, Stahle C, Chu E, Smith GH, Merlino G, et al. Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands. Genes Dev 1992;6:345-355.
40. Dievart A, Beaulieu N, Jolicoeur P. Involvement of Notchl in the development of mouse mammary tumors. Oncogene 1999; 18:5973-5981.
41. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 2002;8:979-986.
42. Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci U S A 1995;92:6414-6418.
43. Politi K, Feirt N, Kitajewski J. Notch in mammary gland development and breast cancer. Semin Cancer Biol 2004;14:341-347.
44. Dotto GP. Notch tumor suppressor function. Oncogene 2008;27:5115-5123.
45. Fuchs E, Raghavan S. Getting under the skin of epidermal morphogenesis. Nat Rev Genet 2002;3:199-209.
46. Lefort K, Dotto GP. Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol 2004;14:374-386.
47. Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B, Miele L. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ 2002;9:842-855.
48. Talora C, Sgroi DC, Crum CP, Dotto GP. Specific down-modulation of Notchl signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev 2002;16:2252-2263.
49. Chu J, Jeffries S, Norton JE, Capobianco AJ, Bresnick EH. Repression of activator protein-1-mediated transcriptional activation by the Notch-1 intracellular domain. J Biol Chem 2002;277:7587-7597.
50. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M, et al. Notchl functions as a tumor suppressor in mouse skin. Nat Genet 2003;33:416-421.
51. Thelu J, Rossio P, Favier B. Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol 2002;2:7.
52. Collins BJ, Kleeberger W, Ball DW. Notch in lung development and lung cancer. Semin Cancer Biol 2004; 14:357-364.
53. Kohler C, Bell AW, Bowen WC, Monga SP, Fleig W, Michalopoulos GK. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration. Hepatology 2004;39:1056-1065.
54. Croquelois A, Blindenbacher A, Terracciano L, Wang X, Langer I, Radtke F, et al. Inducible inactivation of Notchl causes nodular regenerative hyperplasia in mice. Hepatology 2005;41:487-496.
55. Qi R, An H, Yu Y, Zhang M, Liu S, Xu H, et al. Notchl signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis. Cancer Res 2003;63:8323-8329.
56. Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, et al. Notchl Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression. J Biol Chem 2009;284:16183-16190.
57. Maliekal TT, Bajaj J, Giri V, Subramanyam D, Krishna S. The role of Notch signaling in human cervical cancer:implications for solid tumors. Oncogene 2008;27:5110-5114.
58. Parr C, Watkins G, Jiang WG. The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer. Int J Mol Med 2004; 14:779-786.
59. Cavin LG, Venkatraman M, Factor VM, Kaur S, Schroeder I, Mercurio F, et al. Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis. Cancer Res 2004;64:7030-7038.
60. Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res 2001;61:3200-3205.
61. Sarmento LM, Huang H, Limon A, Gordon W, Fernandes J, Tavares MJ, et al. Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kip1 degradation. J Exp Med 2005;202:157-168.
62. Curry CL, Reed LL, Golde TE, Miele L, Nickoloff BJ, Foreman KE. Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells. Oncogene 2005;24:6333-6344.
63. Maillard I, Fang T, Pear WS. Regulation of lymphoid development, differentiation, and function by the Notch pathway. Annu Rev Immunol 2005;23:945-974.
64. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci 2002;25:471-490.
65. Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 2005;8:13-23.