Genetics of hepatocellular carcinoma

World Journal of Gastroenterology

Volumn 13, Issue 16, 2007, Pages 2271-2282

  Teufel, Andreas ^a   Staib, Frank ^a   Kanzler, Stephan ^a   Weinmann, Arndt ^a   Schulze Bergkamen, Henning ^a   Galle, Peter R ^a  

^a JOHANNES GUTENBERG UNIVERSITY   (Germany)

Author keywords

Chromosome; Genetics; Genomics; Hepatocellular carcinoma; Liver cancer; Mutation; Pathway

Indexed keywords

ALPHA INTERFERON; CISPLATIN; COMPLEMENTARY DNA; FLUOROURACIL; HISTONE DEACETYLASE INHIBITOR; PROTEIN P53; RAS PROTEIN; RETINOBLASTOMA PROTEIN; SORAFENIB; TRANSFORMING GROWTH FACTOR BETA; WNT PROTEIN;

CANCER GENETICS; CANCER RISK; CHROMOSOME ABERRATION; CHROMOSOME ANALYSIS; CHROMOSOME SEGREGATION; DNA METHYLATION; DRUG TARGETING; EDITORIAL; ENVIRONMENTAL EXPOSURE; GENE MUTATION; GENE OVEREXPRESSION; GENE TARGETING; GENOMICS; HEPATITIS B VIRUS; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN GENOME; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; PROTEIN FUNCTION; REGULATORY MECHANISM; SIGNAL TRANSDUCTION; WILD TYPE;

EID: 34249845990     PISSN: 10079327     EISSN: None     Source Type: Journal    
DOI: 10.3748/wjg.v13.i16.2271     Document Type: Editorial

References (180)

1. Motola-Kuba D, Zamora-Valdes D, Uribe M, Mendez-Sanchez N. Hepatocellular carcinoma. An overview. Ann Hepatol 2006; 5: 16-24
2. McGlynn KA, London WT. Epidemiology and natural history of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 2005; 19: 3-23
3. Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev 2004; 5: 118-125
4. Teo EK, Fock KM. Hepatocellular carcinoma: an Asian perspective. Dig Dis 2001; 19: 263-268
5. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 2006; 40: S5-S10
6. Moinzadeh P, Breuhahn K, Stutzer H, Schirmacher P. Chromosome alterations in human hepatocellular carcinomas correlate with aetiology and histological grade-results of an explorative CGH meta-analysis. Br J Cancer 2005; 92: 935-941
7. Hofseth LJ, Hussain SP, Harris CC. p53: 25 years after its discovery. Trends Pharmacol Sci 2004; 25: 177-181
8. Ratovitski EA, Patturajan M, Hibi K, Trink B, Yamaguchi K, Sidransky D. p53 associates with and targets Delta Np63 into a protein degradation pathway. Proc Natl Acad Sci USA 2001; 98: 1817-1822
9. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250: 1233-1238
10. Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. Germline transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990; 348: 747-749
11. Harris CC. p53 tumor suppressor gene: from the basic research laboratory to the clinic--an abridged historical perspective. Carcinogenesis 1996; 17: 1187-1198
12. Oren M, Rotter V. Introduction: p53-the first twenty years. Cell Mol Life Sci 1999; 55: 9-11
13. Staib F, Robles AI, Varticovski L, Wang XW, Zeeberg BR, Sirotin M, Zhurkin VB, Hofseth LJ, Hussain SP, Weinstein JN, Galle PR, Harris CC. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res 2005; 65: 10255-10264
14. Sengupta S, Harris CC. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol 2005; 6: 44-55
15. Edamoto Y, Hara A, Biernat W, Terracciano L, Cathomas G, Riehle HM, Matsuda M, Fujii H, Scoazec JY, Ohgaki H. Alterations of RB1, p53 and Wnt pathways in hepatocellular carcinomas associated with hepatitis C, hepatitis B and alcoholic liver cirrhosis. Int J Cancer 2003; 106: 334-341
16. Hainaut P, Hollstein M. p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 2000; 77: 81-137
17. Staib F, Hussain SP, Hofseth LJ, Wang XW, Harris CC. TP53 and liver carcinogenesis. Hum Mutat 2003; 21: 201-216
18. Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991; 350:429-431
19. Haber DA, Housman DE. Rate-limiting steps: the genetics of pediatric cancers. Cell 1991; 64:5-8
20. Scorsone KA, Zhou YZ, Butel JS, Slagle BL. p53 mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res 1992; 52:1635-1638
21. Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P. Geographic variation of p53 mutational profile in nonmalignant human liver. Science 1994; 264: 1317-1319
22. Kress S, Jahn UR, Buchmann A, Bannasch P, Schwarz M. p53 Mutations in human hepatocellular carcinomas from Germany. Cancer Res 1992; 52: 3220-3223
23. Oda T, Tsuda H, Scarpa A, Sakamoto M, Hirohashi S. p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res 1992; 52: 6358-6364
24. Ozturk M. p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet 1991; 338:1356-1359
25. Aguilar F, Hussain SP, Cerutti P. Aflatoxin B1 induces the transversion of G-> T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci USA 1993; 90: 8586-8590
26. Hsu IC, Tokiwa T, Bennett W, Metcalf RA, Welsh JA, Sun T, Harris CC. p53 gene mutation and integrated hepatitis B viral DNA sequences in human liver cancer cell lines. Carcinogenesis 1993; 14: 987-992
27. Puisieux A, Ji J, Guillot C, Legros Y, Soussi T, Isselbacher K, Czturk M. p53-mediated cellular response to DNA damage in cells with replicative hepatitis B virus. Proc Natl Acad Sci USA 1995; 92:1342-1346
28. Hosono S, Chou MJ, Lee CS, Shih C. Infrequent mutation of p53 gene in hepatitis B virus positive primary hepatocellular carcinomas. Oncogene 1993; 8:491-496
29. Jaskiewicz K, Chasen MR. Differential expression of transforming growth factor alpha, adhesions molecules and integrins in primary, metastatic liver tumors and in liver cirrhosis. Anticancer Res 1995; 15: 559-562
30. Teramoto T, Satonaka K, Kitazawa S, Fujimori T, Hayashi K, Maeda S. p53 gene abnormalities are closely related to hepatoviral infections and occur at a late stage of hepatocarcinogenesis. Cancer Res 1994; 54: 231-235
31. Tanaka S, Toh Y, Adachi E, Matsumata T, Mori R, Sugimachi K. Tumor progression in hepatocellular carcinoma may be mediated by p53 mutation. Cancer Res 1993; 53: 2884-2887
32. Oda T, Tsuda H, Sakamoto M, Hirohashi S. Different mutations of the p53 gene in nodule-in-nodule hepatocellular carcinoma as a evidence for multistage progression. Cancer Lett 1994; 83: 197-200
33. Nagai H, Emi M, Terada Y, Baba. M, Shimizu M, Konishi N, Kaneko S, Kobayashi K, Yumoto Y, Ghazizadeh M, Kawanami O, Matsubara K. DNA alterations during multi-step development of human hepatocellular carcinomas revealed by laser capture microdissection. Hepatol Res 2003; 26: 199-208
34. Barbin A. Formation of DNA etheno adducts in rodents and humans and their role in carcinogenesis. Acta Biochim Pol 1998; 45:145-161
35. Barbin A. Etheno-adduct-forming chemicals: from mutagenicity testing to tumor mutation spectra. Mutat Res 2000; 462: 55-69
36. Hollstein M, Marion MJ, Lehman T, Welsh J, Harris CC, Martel-Planche G, Kusters I, Montesano R. p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. Carcinogenesis 1994; 15: 1-3
37. Trivers GE, De Benedetti VM, Cawley HL, Caron G, Harrington AM, Bennett WP, Jett JR, Colby TV, Tazelaar H, Pairolero P, Miller RD, Harris CC. Anti-p53 antibodies in sera from patients with chronic obstructive pulmonary disease can predate a diagnosis of cancer. Clin Cancer Res 1996; 2: 1767-1775
38. Evans DM, Williams WJ, Kung IT. Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers. Histopathology 1983; 7: 377-388
39. Tamburro CH, Makk L, Popper H. Early hepatic histologic alterations among chemical (vinyl monomer) workers. Hepatology 1984; 4: 413-418
40. Weihrauch M, Lehnert G, Kockerling F, Wittekind C, Tannapfel A. p53 mutation pattern in hepatocellular carcinoma in workers exposed to vinyl chloride. Cancer 2000; 88:1030-1036
41. Hussain SP, Raja K, Amstad PA, Sawyer M, Trudel LJ, Wogan GN, Hofseth LJ, Shields PG, Billiar TR, Trautwein C, Hohler T, Galle PR, Phillips DH, Markin R, Marrogi AJ, Harris CC. Increased p53 mutation load in nontumorous human liver of wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA 2000; 97:12770-12775
42. Britton RS. Metal-induced hepatotoxicity. Semin Liver Dis 1996; 16: 3-12
43. Hofseth LJ, Saito S, Hussain SP, Espey MG, Miranda KM, Araki Y, Jhappan C, Higashimoto Y, He P, Linke SP, Quezado MM, Zurer I, Rotter V, Wink DA, Appella E, Harris CC. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci USA 2003; 100: 143-148
44. Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 1994; 91: 2230-2234
45. Schaeffer L, Roy R, Humbert S, Moncollin V, Vermeulen W, Hoeijmakers JH, Chambon P, Egly JM. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science 1993; 260: 58-63
46. Lee SG, Rho HM. Transcriptional repression of the human p53 gene by hepatitis B viral X protein. Oncogene 2000; 19: 468-471
47. Arbuthnot P, Capovilla A, Kew M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol 2000; 15: 357-368
48. Bergsland EK. Molecular mechanisms underlying the development of hepatocellular carcinoma. Semin Oncol 2001; 28: 521-531
49. Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer 1999; 80: 875-879
50. Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, Kumada H, Kawanishi M. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993; 18:47-53
51. You LR, Chen CM, Lee YH. Hepatitis C virus core protein enhances NF-kappaB signal pathway triggering by lymphotoxin-beta receptor ligand and tumor necrosis factor alpha. J Virol 1999; 73: 1672-1681
52. Marusawa H, Hijikata M, Chiba T, Shimotohno K. Hepatitis C virus core protein inhibits Fas- and tumor necrosis factor alpha-mediated apoptosis via NF-kappaB activation. J Virol 1999; 73:4713-4720
53. Block TM, Mehta AS, Fimmel CJ, Jordan R. Molecular viral oncology of hepatocellular carcinoma. Oncogene 2003; 22: 5093-5107
54. Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C, Lai MM. Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 1998; 72: 3691-3697
55. Lu W, Lo SY, Chen M, Wu K, Fung YK, Ou JH. Activation of p53 tumor suppressor by hepatitis C virus core protein. Virology 1999; 264: 134-141
56. Ray RB, Steele R, Meyer K, Ray R. Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem 1997; 272: 10983-10986
57. Honda M, Kaneko S, Kawai H, Shirota Y, Kobayashi K. Differential gene expression between chronic hepatitis B and C hepatic lesion. Gastroenterology 2001; 120: 955-966
58. Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression. Am J Pathol 2002; 160: 641-654
59. Dou J, Liu P, Wang J, Zhang X. Preliminary analysis of gene expression profiles in HepG2 cell line induced by different genotype core proteins of HCV. Cell Mol Immunol 2006; 3: 227-233
60. Dou J, Liu P, Zhang X. Cellular response to gene expression profiles of different hepatitis C virus core proteins in the Huh-7 cell line with microarray analysis. J Nanosci Nanotechnol 2005; 5:1230-1235
61. Fukutomi T, Zhou Y, Kawai S, Eguchi H, Wands JR, Li J. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology 2005; 41: 1096-1105
62. Okada T, Iizuka N, Yamada-Okabe H, Mori N, Tamesa T, Takernoto N, Tangoku A, Hamada. K, Nakayama H, Miyamoto T, Uchimura S, Hamamoto Y, Oka M. Gene expression profile linked to p53 status in hepatitis C virus-related hepatocellular carcinoma. FEBS Lett 2003; 555: 583-590
63. Luu HH, Zhang R, Hayclon RC, Rayburn E, Kang Q, Si W, Park JK, Wang H, Peng Y, Jiang W, He TC. Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets 2004; 4: 653-671
64. Johnson ML, Rajamannan N. Diseases of Wnt signaling. Rev Endocr Metab Disord 2006; 7: 41-49
65. Kelleher FC, Fennelly D, Rafferty M. Common critical pathways in embryogenesis and cancer. Acta Oncol 2006; 45: 375-388
66. Willert K, Jones KA. Wnt signaling: is the party in the nucleus? Genes Dev 2006; 20:1394-1404
67. Janssens N, Janicot M, Perera T. The Wnt-dependent signaling pathways as target in oncology drug discovery. Invest New Drugs 2006; 24:263-280
68. Inagawa S, Itabashi M, Adachi S, Kawamoto T, Hori M, Shimazaki J, Yoshimi F, Fukao K. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res 2002; 8: 450-456
69. Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001; 92: 136-145
70. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 1998; 95:8847-8851
71. Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol 2000; 157: 763-770
72. Mao TL, Chu JS, Jeng YM, Lai PL, Hsu HC. Expression of mutant nuclear beta-catenin correlates with non-invasive hepatoceHular carcinoma, absence of portal vein spread, and good prognosis. J Pathol 2001; 193: 95-101
73. Terris B, Pineau P, Bregeaud L, Valla D, Belghiti J, Tiollais P, Degott C, Dejean A. Close correlation between beta-catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas. Oncogene 1999; 18: 6583-6588
74. Devereux TR, Stern MC, Flake GP, Yu MC, Zhang ZQ, London SJ, Taylor JA. CTNNB1 mutations and beta-catenin protein accumulation in human hepatocellular carcinomas associated with high exposure to aflatoxin B1. Mol Carcinog 2001; 31: 68-73
75. Huang H, Fujii H, Sankila. A, Mahler-Araujo BM, Matsuda M, Cathomas G, Ohgaki H. Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection. Am J Pathol 1999; 155: 1795-1801
76. Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000; 24: 245-250
77. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002; 21: 4863-4871
78. Ishizaki Y, Ikeda S, Fujimori M, Shimizu Y, Kurihara T, Itamoto T, Kikuchi A, Okajima M, Asahara T. Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Int J Oncol 2004; 24: 1077-1083
79. Colnot S, Decaens T, Niwa-Kawakita M, Godard C, Hamard G, Kahn A, Giovannini M, Perret C. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci USA 2004; 101: 17216-17221
80. Merle P, de la Monte S, Kim M, Herrmann M, Tanaka S, Von Dem Bussche A, Kew MC, Trepo C, Wands JR. Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology 2004; 127: 1110-1122
81. Merle P, Kim M, Herrmann M, Gupte A, Lefrancois L, Califano S, Trepo C, Tanaka S, Vitvitski L, de la Monte S, Wands JR. Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol 2005; 43: 854-862
82. Yau TO, Chan CY, Chan KL, Lee MF, Wong CM, Fan ST, Ng IO. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene 2005; 24: 1607-1614
83. Shih YL, Shyu RY, Hsieh CB, Lai HC, Liu KY, Chu TY, Lin YW. Promoter methylation of the secreted frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma. Cancer 2006; 107: 579-590
84. Sangkhathat S, Kusafuka T, Miao J, Yoneda A, Nara K, Yamamoto S, Kaneda Y, Fukuzawa M. In vitro RNA interference against beta-catenin inhibits the proliferation of pediatric hepatic tumors. Int J Oncol 2006; 28: 715-722
85. Oberhammer FA, Pavelka M, Sharma S, Tiefenbacher R, Purchio AF, Bursch W, Schulte-Hermann R. Induction of apoptosis in cultured hepatocytes and in regressing liver by transforming growth factor beta 1. Proc Natl Acad Sci USA 1992; 89: 5408-5412
86. Romero-Gallo J, Sozmen EG, Chytil A, Russell WE, Whitehead R, Parks WT, Holdren MS, Her MF, Gautam S, Magnuson M, Moses HL, Grady WM. Inactivation of TGF-beta signaling in hepatocytes results in an increased proliferative response after partial hepatectomy. Oncogene 2005; 24:3028-3041
87. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67: 753-791
88. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001; 29: 117-129
89. Dumont N, Arteaga. CL. Targeting the TGF beta signaling network in human neoplasia. Cancer Cell 2003; 3: 531-536
90. Abou-Shady M, Baer HU, Friess H, Berberat P, Zimmermann A, Graber H, Gold LI, Korc M, Buchler MW. Transforming growth factor betas and their signaling receptors in human hepatocellular carcinoma. Am J Surg 1999; 177: 209-215
91. Idobe Y, Murawaki Y, Kitamura Y, Kawasaki H. Expression of transforming growth factor-beta 1 in hepatocellular carcinoma in comparison with the non-tumor tissue. Hepatogastroenterology 2003; 50: 54-59
92. Matsuzaki K, Date M, Furukawa F, Tahashi Y, Matsushita M, Sakitani K, Yamashiki N, Seki T, Saito H, Nishizawa M, Fujisawa J, Inoue K. Autocrine stimulatory mechanism by transforming growth factor beta in human hepatocellular carcinoma. Cancer Res 2000; 60: 1394-1402
93. Song BC, Chung YH, Kim JA, Choi WB, Suh DD, Pyo SI, Shin JW, Lee HC, Lee YS, Suh DJ. Transforming growth factor-beta1 as a useful serologic marker of small hepatocellular carcinoma. Cancer 2002; 94: 175-180
94. Tsai JF, Chuang LY, Jeng JE, Yang ML, Chang WY, Hsieh MY, Lin ZY, Tsai JH. Clinical relevance of transforming growth factor-beta 1 in the urine of patients with hepatocellular carcinoma. Medicine (Baltimore) 1997; 76: 213-226
95. Tsai JF, Jeng JE, Chuang LY, Yang ML, Ho MS, Chang WY, Hsieh MY, Lin ZY, Tsai JH. Elevated urinary transforming growth factor-betal level as a tumour marker and predictor of poor survival in cirrhotic hepatocellular carcinoma. Br J Cancer 1997; 76: 244-250
96. Ito N, Kawata S, Tamura S, Shirai Y, Kiso S, Tsushima H, Matsuzawa Y. Positive correlation of plasma transforming growth factor-beta 1 levels with tumor vascularity in hepatocellular carcinoma. Cancer Lett 1995; 89: 45-48
97. Yang YA, Dukhanina O, Tang B, Mamura M, Letterio JJ, MacGregor J, Patel SC, Khozin S, Liu ZY, Green J, Anver MR, Merlino G, Wakefield LM. Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. J Clin Invest 2002; 109: 1607-1615
98. Akhurst RJ, Derynck R. TGF-beta signaling in cancer--a double-edged sword. Trends Cell Biol 2001; 11: S44-S51
99. Wakefield LM, Roberts AB. TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 2002; 12: 22-29
100. Reisenbichler H, Chari RS, Boyer IJ, Jirtle RL. Transforming growth factor-beta receptors type I, II and III in phenobarbital-promoted at liver tumors. Carcinogenesis 1994; 15: 2763-2767
101. Santoni-Rugiu E, Jensen MR, Factor VM, Thorgeirsson SS. Acceleration of c-myc-induced hepatocarcinogenesis by Co-expression of transforming growth factor (TGF)-alpha in transgenic mice is associated with TGF-beta1 signaling disruption. Am J Pathol 1999; 154:1693-1700
102. Kanzler S, Meyer E, Lohse AW, Schirmacher P, Henninger J, Galle PR, Blessing M. Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis. Oncogene 2001; 20: 5015-5024
103. Tang B, Bottinger EP, Jakowlew SB, Bagnall KM, Mariano J, Anver MR, Letterio JJ, Wakefield LM. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med 1998; 4: 802-807
104. Im YH, Kim HT, Kim IY, Factor VM, Halm KB, Anzano M, Jang JJ, Flanders K, Haines DC, Thorgeirsson SS, Sizeland A, Kim SJ. Heterozygous mice for the transforming growth factor-beta type II receptor gene have increased susceptibility to hepatocellular carcinogenesis. Cancer Res 2001; 61: 6665-6668
105. Ueno T, Hashimoto O, Kimura R, Torimura T, Kawaguchi T, Nakamura T, Sakata R, Koga H, Sata M. Relation of type II transforming growth factor-beta receptor to hepatic fibrosis and hepatocellular carcinoma. Int J Oncol 2001; 18: 49-55
106. Steiner MS, Barrack ER. Transforming growth factor-beta 1 overproduction in prostate cancer: effects on growth in vivo and in vitro. Mol Endocrinol 1992; 6: 15-25
107. Iyer S, Wang ZG, Akhtari M, Zhao W, Seth P. Targeting TGFbeta signaling for cancer therapy. Cancer Biol Ther 2005; 4: 261-266
108. Park YN, Chae KJ, Oh BK, Choi J, Choi KS, Park C. Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism to transforming growth factor-beta. Hepatogastroenterology 2004; 51: 396-400
109. Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 1999; 18: 4879-4883
110. Zimonjic DB, Durkin ME, Keck-Waggoner CL, Park SW, Thorgeirsson SS, Popescu NC. SMAD5 gene expression, rearrangements, copy number, and amplification at fragile site FRA5C in human hepatocellular carcinoma. Neoplasia 2003; 5: 390-396
111. He J, Tegen SB, Krawitz AR, Martin GS, Luo K. The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins. J Biol Chem 2003; 278: 30540-30547
112. Barbacid M. ras genes. Annu Rev Biochem 1987; 56: 779-827
113. Bourne HR, Wrischnik L, Kenyon C. Ras proteins. Some signal developments. Nature 1990; 348: 678-679
114. Boguski MS, McCorndck F. Proteins regulating Ras and its relatives. Nature 1993; 366: 643-654
115. Quilliam LA, Khosravi-Far R, Huff SY, Der CJ. Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays 1995; 17: 395-404
116. Satoh T, Kaziro Y. Ras in signal transduction. Semin Cancer Biol 1992; 3: 169-177
117. Reuther GW, Der CJ. The Ras branch of small GTPases: Ras family members don't fall far from the tree. Curr Opin Cell Biol 2000; 12: 157-165
118. Clark GJ, Quilliam LA, Hisaka MM, Der CJ. Differential antagonism of Ras biological activity by catalytic and Src homology domains of Ras GTPase activation protein. Proc Natl Acad Sci USA 1993; 90:4887-4891
119. Moodie SA, Wolfman A. The 3Rs of life: Ras, Raf and growth regulation. Trends Genet 1994; 10: 44-48
120. Van Aelst L, Barr M, Marcus S, Polverino A, Wigler M. Complex formation between RAS and RAF and other protein kinases. Proc Natl Acad Sci USA 1993; 90: 6213-6217
121. Moodie SA, Willumsen BM, Weber MJ, Wolfman A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 1993; 260: 1658-1661
122. Zhang XF, Settleman J, Kyriakis JM, Takeuchi-Suzuki E, Elledge SJ, Marshall MS, Bruder JT, Rapp UR, Avruch J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 1993; 364: 308-313
123. Warne PH, Viciana PR, Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 1993; 364: 352-355
124. Vojtek AB, Hollenberg SM, Cooper JA. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 1993; 74:205-214
125. Morrison DK, Cutler RE. The complexity of Raf-1 regulation. Curr Opin Cell Biol 1997; 9:174-179
126. Marais R, Wynne J, Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 1993; 73: 381-393
127. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol 2002; 4: E131-E136
128. Jagirdar J, Nonomura A, Patil J, Thor A, Paronetto F. ras oncogene p21 expression in hepatocellular carcinoma. J Exp Pathol 1989; 4:37-46
129. Nonomura A, Ohta G, Hayashi M, Izumi R, Watanabe K, Takayanagi N, Mizukami Y, Matsubara F. Immunohistochemical detection of ras oncogene p21 product in liver cirrhosis and hepatocellular carcinoma. Am J Gastroenterol 1987; 82: 512-518
130. Schnierer MM, Bataille F, Weiss TS, Hellerbrand C, Bosserhoff AK. Raf kinase inhibitor protein is downregulated in hepatocellular carcinoma. Oncol Rep 2006; 16:451-456
131. Tsuda H, Hirohashi S, Shimosato Y, Ino Y, Yoshida T, Terada M. Low incidence of point mutation of c-Ki-ras and N-ras oncogenes in human hepatocellular carcinoma. Jpn J Cancer Res 1989; 80: 196-199
132. Takada S, Koike K. Activated N-ras gene was found in human hepatoma tissue but only in a small fraction of the tumor cells. Oncogene 1989; 4: 189-193
133. Challen C, Guo K, Collier JD, Cavanagh D, Bassendine MF. Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. J Hepatol 1992; 14: 342-346
134. Cerutti P, Hussain P, Pourzand C, Aguilar F. Mutagenesis of the H-ras protooncogene and the p53 tumor suppressor gene. Cancer Res 1994; 54: 1934s-1938s
135. Boix-Ferrero J, Pellin A, Blesa JR, Adrados M, Llombart-Bosch A. K-ras Gene Mutations in Liver Carcinomas from a Mediterranean Area of Spain. Int J Surg Pathol 2000; 8: 267-270
136. Soman NR, Wogan GN. Activation of the c-Ki-ras oncogene in aflatoxin B1-induced hepatocellular carcinoma and adenoma in the rat: detection by denaturing gradient gel electrophoresis. Proc Natl Acad Sci USA 1993; 90: 2045-2049
137. Bai F, Nakanishi Y, Takayama K, Pei XH, Inoue K, Harada T, Izumi M, Hara N. Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice. Teratog Carcinog Mutagen 2003; Suppl. 1: 161-170
138. Baba M, Yamamoto R, Iishi H, Tatsuta M. Ha-ras mutations in N-nitrosomorpholine-induced lesions and inhibition of hepatocarcinogenesis by antisense sequences in rat liver. Int J Cancer 1997; 72: 815-820
139. Watatani M, Perantoni AO, Reed CD, Enomoto T, Wenk ML, Rice JM. Infrequent activation of K-ras, H-ras, and other oncogenes in hepatocellular neoplasms initiated by methyl (acetoxymethyl) nitrosamine, a methylating agent, and promoted by phenobarbital in F344 rats. Cancer Res 1989; 49: 1103-1109
140. Li H, Lee GH, Liu J, Nomura K, Ohtake K, Kitagawa T. Low frequency of ras activation in 2-acetylaminofluorene-and 3′-methyl-4-(dimethylamino) azobenzene-induced rat hepatocellular carcinomas. Cancer Lett 1991; 56: 17-24
141. Yamamoto S, Mitsumori K, Kodama Y, Matsunuma N, Manabe S, Okamiya H, Suzuki H, Fukuda T, Sakamaki Y, Sunaga M, Nomura G, Hioki K, Wakana S, Nomura T, Hayashi Y. Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice. Carcinogenesis 1996; 17: 2455-2461
142. Weihrauch M, Benick M, Lehner G, Wittekind M, Bader M, Wrbitzk R, Tannapfel A. High prevalence of K-ras-2 mutations in hepatocellular carcinomas in workers exposed to vinyl chloride. Int Arch Occup Environ Health 2001; 74: 405-410
143. Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k-ras-2 mutations and p16 (INK4A) methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer 2001; 84: 982-989
144. Liao Y, Tang ZY, Ye SL, Liu KD, Sun FX, Huang Z. Modulation of apoptosis, tumorigenesity and metastatic potential with antisense H-ras oligodeoxynucleotides in a high metastatic tumor model of hepatoma: LCI-D20. Hepatogastroenterology 2000; 47: 365-370
145. Liao Y, Tang ZY, Liu KD, Ye SL, Huang Z. Apoptosis of human BEL-7402 hepatocellular carcinoma cells released by antisense H-ras DNA--in vitro and in vivo studies. J Cancer Res Clin Oncol 1997; 123: 25-33
146. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 4293-4300
147. Das SK, Hashimoto T, Shimizu K, Yoshida T, Sakai T, Sowa Y, Komoto A, Kanazawa K. Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through upregulation of p21WAF1/Cip1. Biochim Biophys Acta 2005; 1726: 328-335
148. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res 2002; 89: 213-228
149. Bartkova J, Lukas C, Sorensen CS, Meyts ER, Skakkebaek NE, Lukas J, Bartek J. Deregulation of the RB pathway in human testicular germ cell tumours. J Pathol 2003; 200: 149-156
150. Bartkova J, Rajpert-De Meyts E, Skakkebaek NE, Lukas J, Bartek J. Deregulation of the G1/S-phase control in human testicular germ cell tumours. APMIS 2003; 111: 252-265; discussion 265-266
151. Korenjak M, Brehm A. E2F-Rb complexes regulating transcription of genes important for differentiation and development. Curr Opin Genet Dev 2005; 15: 520-527
152. De Veylder L, Joubes J, Inze D. Plant cell cycle transitions. Curr Opin Plant Biol 2003; 6: 536-543
153. Dannenberg JH, te Riele HP. The retinoblastoma gene family in cell cycle regulation and suppression of tumorigenesis. Results Probl Cell Differ 2006; 42: 183-225
154. Barbosa MS, Edmonds C, Fisher C, Schiller JT, Lowy DR, Vousden KH. The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation. EMBO J 1990; 9: 153-160
155. Hagemeier C, Caswell R, Hayhurst G, Sinclair J, Kouzarides T. Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J 1994; 13: 2897-2903
156. DeCaprio JA, Ludlow JW, Figge J, Shew JY, Huang CM, Lee WH, Marsilio E, Paucha E, Livingston DM. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 1988; 54: 275-283
157. Suh SI, Pyun HY, Cho JW, Baek WK, Park JB, Kwon T, Park JW, Suh MH, Carson DA. 5-Aza-2′-deoxycytidine leads to down-regulation of aberrant p16INK4A RNA transcripts and restores the functional retinoblastoma protein pathway in hepatocellular carcinoma cell lines. Cancer Lett 2000; 160: 81-88
158. Azechi H, Nishida N, Fukuda Y, Nishimura T, Minata M, Katsuma H, Kuno M, Ito T, Komeda T, Kita R, Takahashi R, Nakao K. Disruption of the p16/cyclin D1/retinoblastoma protein pathway in the majority of human hepatocellular carcinomas. Oncology 2001; 60: 346-354
159. Joo M, Kang YK, Kim MR, Lee HK, Jang JJ. Cyclin D1 overexpression in hepatocellular carcinoma. Liver 2001; 21: 89-95
160. Hui AM, Sakamoto M, Kanai Y, Ino Y, Gotoh M, Yokota J, Hirohashi S. Inactivation of p16INK4 in hepatocellular carcinoma. Hepatology 1996; 24: 575-579
161. Nam SW, Lee JH, Noh JH, Lee SN, Kim SY, Lee SH, Park CK, Ahn YM, Park WS, Yoo NJ, Lee JY. Comparative analysis of expression profiling of early-stage carcinogenesis using nodule-in-nodule-type hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2006; 18: 239-247
162. Shao RX, Hoshida Y, Otsuka M, Kato N, Tateishi R, Teratani T, Shiina S, Taniguchi H, Moriyama M, Kawabe T, Omata M. Hepatic gene expression profiles associated with fibrosis progression and hepatocarcinogenesis in hepatitis C patients. World J Gastroenterol 2005; 11: 1995-1999
163. Kim JW, Ye Q, Forgues M, Chen Y, Budhu A, Sime J, Hofseth LJ, Kaul R, Wang XW. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology 2004; 39: 518-527
164. Okamoto M, Utsunomiya T, Wakiyama S, Hashimoto M, Fukuzawa K, Ezaki T, Hanai T, Inoue H, Mori M. Specific gene-expression profiles of noncancerous liver tissue predict the risk for multicentric occurrence of hepatocellular carcinoma in hepatitis C virus-positive patients. Ann Surg Oncol 2006; 13: 947-954
165. Yang LY, Wang W, Peng JX, Yang JQ, Huang GW. Differentially expressed genes between solitary large hepatocellular carcinoma and nodular hepatocellular carcinoma. World J Gastroenterol 2004; 10: 3569-3573
166. Budhu AS, Zipser B, Forgues M, Ye QH, Sun Z, Wang XW. The molecular signature of metastases of human hepatocellular carcinoma. Oncology 2005; 69 Suppl 1: 23-27
167. Iizuka N, Oka M, Yamada-Okabe H, Nishida M, Maeda Y, Mori N, Takao T, Tamesa T, Tangoku A, Tabuchi H, Hamada K, Nakayama H, Ishitsuka H, Miyamoto T, Hirabayashi A, Uchimura S, Hamamoto Y. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 2003; 361: 923-929
168. Lee JS, Thorgeirsson SS. Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets. Gastroenterology 2004; 127: S51-S55
169. Stahl S, Ittrich C, Marx-Stoelting P, Kohle C, Altug-Teber O, Riess O, Bonin M, Jobst J, Kaiser S, Buchmann A, Schwarz M. Genotype-phenotype relationships in hepatocellular tumors from mice and man. Hepatology 2005; 42: 353-361
170. Iizuka N, Oka M, Yamada-Okabe H, Mori N, Tamesa T, Okada T, Takemoto N, Tangoku A, Hamada K, Nakayama H, Miyarnoto T, Uchimura S, Hamamoto Y. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 2002; 62: 3939-3944
171. Chung EJ, Sung YK, Farooq M, Kim Y, Im. S, Tak WY, Hwang YJ, Kim YI, Han HS, Kim JC, Kim MK. Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray. Mol Cells 2002; 14: 382-387
172. Moriyama M, Hoshida Y, Otsuka M, Nishimura S, Kato N, Goto T, Taniguchi H, Shiratori Y, Seki N, Omata M. Relevance network between chemosensitivity and transcriptome in human hepatorna cells. Mol Cancer Ther 2003; 2: 99-205
173. Hoshida Y, Moriyama M, Otsuka M, Kato N, Goto T, Taniguchi H, Shiratori Y, Seki N, Omata M. Identification of genes associated with sensitivity to 5-fluorouracil and cisplatin in hepatoma cells. J Gastroenterol 2002; 37 Suppl 14: 92-95
174. Moriyama M, Hoshida Y, Kato N, Otsuka M, Yoshida H, Kawabe T, Omata M. Genes associated with human hepatocellular carcinoma cell chemosensitivity to 5-fluorouracil plus interferon-alpha combination chemotherapy. Int Oncol 2004; 25: 1279-1287
175. Wong N, Chan KY, Macgregor PF, Lai PB, Squire JA, Beheshti B, Albert M, Leung TW. Transcriptional profiling identifies gene expression changes associated with IFN-alpha tolerance in hepatitis C-related hepatocellular carcinoma cells. Clin Cancer Res 2005; 11: 1319-1326
176. Gray SG, Qian CN, Furge K, Guo X, Teh BT. Microarray profiling of the effects of histone deacetylase inhibitors on gene expression in cancer cell lines. Int J Oncol 2004; 24: 773-795
177. Chiba T, Yokosuka O, Fukai K, Kojima H, Tada M, Arai M, Imazeki F, Saisho H. Cell growth inhibition and gene expression induced by the histone deacetylase inhibitor, trichostatin A, on human hepatoma cells. Oncology 2004; 66: 481-491
178. Yeo W, Wong N, Wong WL, Lai PB, Zhong S, Johnson PJ. High frequency of promoter hypermethylation of RASSF1A in tumor and plasma of patients with hepatocellular carcinoma. Liver Int 2005; 25: 266-272
179. Yu J, Zhang HY, Ma ZZ, Lu W, Wang YF, Zhu JD. Methylation profiling of twenty four genes and the concordant methylation behaviours of nineteen genes that may contribute to hepatocellular carcinogenesis. Cell Res 2003; 13: 319-333
180. Wong IH, Johnson PJ, Lai PB, Lau WY, Lo YM. Tumor-derived epigenetic changes in the plasma and serum of liver cancer patients. Implications for cancer detection and monitoring. Ann N Y Acad Sci 2000; 906: 102-105