Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances.

F1000Research

Volumn 5, Issue , 2016, Pages

  Dhanasekaran, Renumathy ^a   Bandoh, Salome ^b   Roberts, Lewis R ^c  

^a STANFORD UNIVERSITY   (United States)

^b KORLE BU TEACHING HOSPITAL   (Ghana)

^c MAYO CLINIC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BETA CATENIN; LONG UNTRANSLATED RNA; MICRORNA; NIVOLUMAB; PROTEIN P53; PROTEIN TYROSINE KINASE; SORAFENIB; STAT PROTEIN; TELOMERASE; TRANSFORMING GROWTH FACTOR BETA; UBIQUITIN; VASCULOTROPIN; WNT PROTEIN;

CANCER CLASSIFICATION; CANCER GROWTH; CANCER STEM CELL; CARCINOGENESIS; CHROMATIN ASSEMBLY AND DISASSEMBLY; COPY NUMBER VARIATION; DNA MODIFICATION; DRUG EFFICACY; GENE AMPLIFICATION; GENE DELETION; GENE FREQUENCY; GENE MUTATION; GENE REARRANGEMENT; HEPATITIS B VIRUS; HISTONE MODIFICATION; HISTOPATHOLOGY; HUMAN; LIVER CELL CARCINOMA; MOLECULAR PATHOLOGY; NONHUMAN; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRECANCER; PROMOTER REGION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; SOMATIC MUTATION; TUMOR SUPPRESSOR GENE; VIRUS DNA CELL DNA INTERACTION; WNT SIGNALING PATHWAY;

EID: 85010850447     PISSN: None     EISSN: 20461402     Source Type: Journal    
DOI: 10.12688/F1000RESEARCH.6946.1     Document Type: Review

References (150)

1. Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5): E359-86.
2. Mittal S, El-Serag HB: Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013; 47(Suppl): S2-6.
3. Shlomai A, de Jong YP, Rice CM: Virus associated malignancies: the role of viral hepatitis in hepatocellular carcinoma. Semin Cancer Biol. 2014; 26: 78-88.
4. Nordenstedt H, White DL, El-Serag HB: The changing pattern of epidemiology in hepatocellular carcinoma. Dig Liver Dis. 2010; 42(Suppl 3): S206-14.
5. Hutchinson SJ, Bird SM, Goldberg DJ: Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis. Clin Gastroenterol Hepatol. 2005; 3(11): 1150-1159.
6. Loomba R, Yang HI, Su J, et al.: Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study. Am J Epidemiol. 2013; 177(4): 333-342.
7. Wong RJ, Cheung R, Ahmed A: Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014; 59(6): 2188-2195.
8. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010; 51(6): 1972-1978.
9. Nair S, Mason A, Eason J, et al.: Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology. 2002; 36(1): 150-155.
10. Shebl FM, El-Kamary SS: Diabetes mellitus, obesity, and hepatocellular carcinoma: the jury is still out. Am J Gastroenterol. 2010; 105(9): 2116-2117.
11. Regimbeau JM, Colombat M, Mognol P, et al.: Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl. 2004; 10(2 Suppl 1): S69-73.
12. Welzel TM, Graubard BI, Zeuzem S, et al.: Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEERMedicare database. Hepatology. 2011; 54(2): 463-471.
13. The International Consensus Group for Hepatocellular Neoplasia: Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology. 2009; 49(2): 658-664.
14. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014; 343(6174): 1010-1014.
15. Graham RP, Jin L, Knutson DL, et al.: DNAJB1-PRKACA is specific for fibrolamellar carcinoma. Mod Pathol. 2015; 28(6): 822-829.
16. Wood LD, Heaphy CM, Daniel HD, et al.: Chromophobe hepatocellular carcinoma with abrupt anaplasia: a proposal for a new subtype of hepatocellular carcinoma with unique morphological and molecular features. Mod Pathol. 2013; 26(12): 1586-1593.
17. Li S, Mao M: Next generation sequencing reveals genetic landscape of hepatocellular carcinomas. Cancer Lett. 2013; 340(2): 247-253.
18. Machida K, Cheng KT, Sung VM, et al.: Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A. 2004; 101(12): 4262-4267.
19. Poon SL, Pang ST, McPherson JR, et al.: Genome-wide mutational signatures of aristolochic acid and its application as a screening tool. Sci Transl Med. 2013; 5(197): 197ra101.
20. Calado RT, Brudno J, Mehta P, et al.: Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology. 2011; 53(5): 1600-1607.
21. Hartmann D, Srivastava U, Thaler M, et al.: Telomerase gene mutations are associated with cirrhosis formation. Hepatology. 2011; 53(5): 1608-1617.
22. Stewart SA, Weinberg RA: Telomerase and human tumorigenesis. Semin Cancer Biol. 2000; 10(6): 399-406.
23. Killela PJ, Reitman ZJ, Jiao Y, et al.: TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013; 110(15): 6021-6026.
24. Nault JC, Mallet M, Pilati C, et al.: High frequency of telomerase reversetranscriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013; 4: 2218.
25. Chen YL, Jeng YM, Chang CN, et al.: TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection. Int J Surg. 2014; 12(7): 659-665.
26. Schulze K, Imbeaud S, Letouzé E, et al.: Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015; 47(5): 505-511.
27. Paterlini-Bréchot P, Saigo K, Murakami Y, et al.: Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene. 2003; 22(25): 3911-3916.
28. Ferber MJ, Montoya DP, Yu C, et al.: Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene. 2003; 22(24): 3813-3820.
29. Totoki Y, Tatsuno K, Covington KR, et al.: Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014; 46(12): 1267-1273.
30. Hussain SP, Schwank J, Staib F, et al.: TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007; 26(15): 2166-2176.
31. Cleary SP, Jeck WR, Zhao X, et al.: Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology. 2013; 58(5): 1693-1702.
32. Guichard C, Amaddeo G, Imbeaud S, et al.: Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012; 44(6): 694-698.
33. Kan Z, Zheng H, Liu X, et al.: Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013; 23(9): 1422-1433.
34. Ozturk M: p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet. 1991; 338(8779): 1356-1359.
35. Madden CR, Finegold MJ, Slagle BL: Altered DNA mutation spectrum in aflatoxin b1-treated transgenic mice that express the hepatitis B virus x protein. J Virol. 2002; 76(22): 11770-11774.
36. Villanueva A, Llovet JM: Liver cancer in 2013: Mutational landscape of HCC-the end of the beginning. Nat Rev Clin Oncol. 2014; 11(2): 73-74.
37. Jiang Z, Jhunjhunwala S, Liu J, et al.: The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients. Genome Res. 2012; 22(4): 593-601.
38. Hai H, Tamori A, Kawada N: Role of hepatitis B virus DNA integration in human hepatocarcinogenesis. World J Gastroenterol. 2014; 20(20): 6236-6243.
39. Sung WK, Zheng H, Li S, et al.: Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012; 44(7): 765-769.
40. Wang J, Chenivesse X, Henglein B, et al.: Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature. 1990; 343(6258): 555-557.
41. Saigo K, Yoshida K, Ikeda R, et al.: Integration of hepatitis B virus DNA into the myeloid/lymphoid or mixed-lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma. Hum Mutat. 2008; 29(5): 703-708.
42. Wang Y, Lau SH, Sham JS, et al.: Characterization of HBV integrants in 14 hepatocellular carcinomas: association of truncated X gene and hepatocellular carcinogenesis. Oncogene. 2004; 23(1): 142-148.
43. Hino O, Kajino K, Umeda T, et al.: Understanding the hypercarcinogenic state in chronic hepatitis: a clue to the prevention of human hepatocellular carcinoma. J Gastroenterol. 2002; 37(11): 883-887.
44. Tokino T, Fukushige S, Nakamura T, et al.: Chromosomal translocation and inverted duplication associated with integrated hepatitis B virus in hepatocellular carcinomas. J Virol. 1987; 61(12): 3848-3854.
45. Wang K, Lim HY, Shi S, et al.: Genomic landscape of copy number aberrations enables the identification of oncogenic drivers in hepatocellular carcinoma. Hepatology. 2013; 58(2): 706-717.
46. Woo HG, Park ES, Lee JS, et al.: Identification of potential driver genes in human liver carcinoma by genomewide screening. Cancer Res. 2009; 69(9): 4059-4066.
47. Jia D, Wei L, Guo W, et al.: Genome-wide copy number analyses identified novel cancer genes in hepatocellular carcinoma. Hepatology. 2011; 54(4): 1227-1236.
48. Wang X, Zhao BS, Roundtree IA, et al.: N6-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015; 161(6): 1388-1399.
49. Tischoff I, Tannapfe A: DNA methylation in hepatocellular carcinoma. World J Gastroenterol. 2008; 14(11): 1741-1748.
50. Park IY, Sohn BH, Yu E, et al.: Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein. Gastroenterology. 2007; 132(4): 1476-1494.
51. Lim JS, Park SH, Jang KL: Hepatitis C virus Core protein overcomes stressinduced premature senescence by down-regulating p16 expression via DNA methylation. Cancer Lett. 2012; 321(2): 154-161.
52. Deng YB, Nagae G, Midorikawa Y, et al.: Identification of genes preferentially methylated in hepatitis C virus-related hepatocellular carcinoma. Cancer Sci. 2010; 101(6): 1501-1510.
53. Su PF, Lee TC, Lin PJ, et al.: Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma. Int J Cancer. 2007; 121(6): 1257-1264.
54. Narimatsu T, Tamori A, Koh N, et al.: p16 promoter hypermethylation in human hepatocellular carcinoma with or without hepatitis virus infection. Intervirology. 2004; 47(1): 26-31.
55. Wong IH, Lo YM, Zhang J, et al.: Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999; 59(1): 71-73.
56. Zhang YJ, Ahsan H, Chen Y, et al.: High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma. Mol Carcinog. 2002; 35(2): 85-92.
57. Zhong S, Tang MW, Yeo W, et al.: Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. Clin Cancer Res. 2002; 8(4): 1087-1092.
58. Bakker J, Lin X, Nelson WG: Methyl-CpG binding domain protein 2 represses transcription from hypermethylated pi-class glutathione S-transferase gene promoters in hepatocellular carcinoma cells. J Biol Chem. 2002; 277(25): 22573-22580.
59. Niwa Y, Kanda H, Shikauchi Y, et al.: Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene. 2005; 24(42): 6406-6417.
60. Zhang YJ, Chen Y, Ahsan H, et al.: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1-DNA adducts and p53 mutation in hepatocellular carcinoma. Int J Cancer. 2003; 103(4): 440-444.
61. Yang JD, Seol SY, Leem SH, et al.: Genes associated with recurrence of hepatocellular carcinoma: integrated analysis by gene expression and methylation profiling. J Korean Med Sci. 2011; 26(11): 1428-1438.
62. Hlady RA, Tiedemann RL, Puszyk W, et al.: Epigenetic signatures of alcohol abuse and hepatitis infection during human hepatocarcinogenesis. Oncotarget. 2014; 5(19): 9425-9443.
63. Villanueva A, Portela A, Sayols S, et al.: DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology. 2015; 61(6): 1945-1956.
64. He C, Xu J, Zhang J, et al.: High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma. Hum Pathol. 2012; 43(9): 1425-1435.
65. Cai MY, Hou JH, Rao HL, et al.: High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med. 2011; 17(1-2): 12-20.
66. Cougot D, Wu Y, Cairo S, et al.: The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription. J Biol Chem. 2007; 282(7): 4277-4287.
67. Fujimoto A, Totoki Y, Abe T, et al.: Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet. 2012; 44(7): 760-764.
68. Li M, Zhao H, Zhang X, et al.: Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet. 2011; 43(9): 828-829.
69. Cao R, Wang L, Wang H, et al.: Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002; 298(5595): 1039-1043.
70. Simon JA, Kingston RE: Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 2009; 10(10): 697-708.
71. Caretti G, Di Padova M, Micales B, et al.: The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 2004; 18(21): 2627-2638.
72. Cheng AS, Lau SS, Chen Y, et al.: EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. Cancer Res. 2011; 71(11): 4028-4039.
73. Sudo T, Utsunomiya T, Mimori K, et al.: Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer. 2005; 92(9): 1754-1758.
74. Au SL, Wong CC, Lee JM, et al.: Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology. 2012; 56(2): 622-631.
75. Jiang J, Gusev Y, Aderca I, et al.: Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res. 2008; 14(2): 419-427.
76. Bala S, Tilahun Y, Taha O, et al.: Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection. J Transl Med. 2012; 10: 151.
77. Villanueva RA, Jangra RK, Yi M, et al.: miR-122 does not modulate the elongation phase of hepatitis C virus RNA synthesis in isolated replicase complexes. Antiviral Res. 2010; 88(1): 119-123.
78. Xu J, Zhu X, Wu L, et al.: MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/β-catenin pathway. Liver Int. 2012; 32(5): 752-760.
79. Tsai WC, Hsu PW, Lai TC, et al.: MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology. 2009; 49(5): 1571-1582.
80. Fornari F, Gramantieri L, Giovannini C, et al.: MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2009; 69(14): 5761-5767.
81. Tsai WC, Hsu SD, Hsu CS, et al.: MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012; 122(8): 2884-2897.
82. Wang Y, Lee CG: Role of miR-224 in hepatocellular carcinoma: a tool for possible therapeutic intervention? Epigenomics. 2011; 3(2): 235-243.
83. Wang Y, Ren J, Gao Y, et al.: MicroRNA-224 targets SMAD family member 4 to promote cell proliferation and negatively influence patient survival. PLoS One. 2013; 8(7): e68744.
84. Sun J, Lu H, Wang X, et al.: MicroRNAs in hepatocellular carcinoma: regulation, function, and clinical implications. ScientificWorldJournal. 2013; 2013: 924206.
85. Kota J, Chivukula RR, O'Donnell KA, et al.: Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009; 137(6): 1005-1017.
86. Du Y, Kong G, You X, et al.: Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J Biol Chem. 2012; 287(31): 26302-26311.
87. Xie H, Ma H, Zhou D: Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma. Biomed Res Int. 2013; 2013: 136106.
88. Yang F, Zhang L, Huo XS, et al.: Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology. 2011; 54(5): 1679-1689.
89. Huang JF, Guo YJ, Zhao CX, et al.: Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin. Hepatology. 2013; 57(5): 1882-1892.
90. Yuan SX, Yang F, Yang Y, et al.: Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients' poor recurrence-free survival after hepatectomy. Hepatology. 2012; 56(6): 2231-2241.
91. Lay AJ, Jiang XM, Kisker O, et al.: Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase. Nature. 2000; 408(6814): 869-873.
92. Yang Z, Zhou L, Wu LM, et al.: Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011; 18(5): 1243-1250.
93. Geng YJ, Xie SL, Li Q, et al.: Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res. 2011; 39(6): 2119-2128.
94. Li G, Zhang H, Wan X, et al.: Long noncoding RNA plays a key role in metastasis and prognosis of hepatocellular carcinoma. Biomed Res Int. 2014; 2014: 780521.
95. Lau CC, Sun T, Ching AK, et al.: Viral-human chimeric transcript predisposes risk to liver cancer development and progression. Cancer cell. 2014; 25(3): 335-349.
96. Lai MC, Yang Z, Zhou L, et al.: Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol. 2012; 29(3): 1810-1816.
97. Quagliata L, Matter MS, Piscuoglio S, et al.: Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology. 2014; 59(3): 911-923.
98. Braconi C, Kogure T, Valeri N, et al.: microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene. 2011; 30(47): 4750-4756.
99. Whittaker S, Marais R, Zhu AX: The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene. 2010; 29(36): 4989-5005.
100. Miamen AG, Dong H, Roberts LR: Immunotherapeutic approaches to hepatocellular carcinoma treatment. Liver Cancer. 2012; 1(3-4): 226-237.
101. Thompson MD, Monga SP: WNT/beta-catenin signaling in liver health and disease. Hepatology. 2007; 45(5): 1298-1305.
102. Hoshida Y, Nijman SM, Kobayashi M, et al.: Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009; 69(18): 7385-7392.
103. Pez F, Lopez A, Kim M, et al.: Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013; 59(5): 1107-1117.
104. Lachenmayer A, Alsinet C, Savic R, et al.: Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib. Clin Cancer Res. 2012; 18(18): 4997-5007.
105. Kim M, Lee HC, Tsedensodnom O, et al.: Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells. J Hepatol. 2008; 48(5): 780-791.
106. Merle P, de La Monte S, Kim M, et al.: Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology. 2004; 127(4): 1110-1122.
107. Shih YL, Shyu RY, Hsieh CB, et al.: Promoter methylation of the secreted frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma. Cancer. 2006; 107(3): 579-590.
108. Villanueva A, Newell P, Chiang DY, et al.: Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007; 27(1): 55-76.
109. Roberts LR, Gores GJ: Hepatocellular carcinoma: molecular pathways and new therapeutic targets. Semin Liver Dis. 2005; 25(2): 212-225.
110. Bhat M, Sonenberg N, Gores GJ: The mTOR pathway in hepatic malignancies. Hepatology. 2013; 58(2): 810-818.
111. Liu L, Cao Y, Chen C, et al.: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006; 66(24): 11851-11858.
112. Tanabe KK, Lemoine A, Finkelstein DM, et al.: Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA. 2008; 299(1): 53-60.
113. Kaposi-Novak P, Lee JS, Gòmez-Quiroz L, et al.: Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest. 2006; 116(6): 1582-1595.
114. Llovet JM, Peña CE, Lathia CD, et al.: Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012; 18(8): 2290-2300.
115. French DM, Lin BC, Wang M, et al.: Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One. 2012; 7(5): e36713.
116. Desnoyers LR, Pai R, Ferrando RE, et al.: Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene. 2008; 27(1): 85-97.
117. Hagel M, Miduturu C, Sheets M, et al.: First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015; 5(4): 424-437.
118. Dhanasekaran R, Nakamura I, Hu C, et al.: Activation of the transforming growth factor-β/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma. Hepatology. 2015; 61(4): 1269-1283.
119. Lai JP, Oseini AM, Moser CD, et al.: The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation. Hepatology. 2010; 52(5): 1680-1689.
120. Lai JP, Sandhu DS, Yu C, et al.: Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma. Hepatology. 2008; 47(4): 1211-1222.
121. Yoshiji H, Kuriyama S, Noguchi R, et al.: Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut. 2005; 54(12): 1768-1775.
122. Park YN, Kim YB, Yang KM, et al.: Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med. 2000; 124(7): 1061-1065.
123. Muto J, Shirabe K, Sugimachi K, et al.: Review of angiogenesis in hepatocellular carcinoma. Hepatol Res. 2015; 45(1): 1-9.
124. Kim KW, Bae SK, Lee OH, et al.: Insulin-like growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res. 1998; 58(2): 348-351.
125. Cannito S, Turato C, Paternostro C, et al.: Hypoxia up-regulates SERPINB3 through HIF-2a in human liver cancer cells. Oncotarget. 2015; 6(4): 2206-2221.
126. Luo D, Wang Z, Wu J, et al.: The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int. 2014; 2014: 409272.
127. Roberts AB, Wakefield LM: The two faces of transforming growth factor beta in carcinogenesis. Proc Natl Acad Sci U S A. 2003; 100(15): 8621-8623.
128. Coulouarn C, Factor VM, Thorgeirsson SS: Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology. 2008; 47(6): 2059-2067.
129. Giannelli G, Bergamini C, Fransvea E, et al.: Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology. 2005; 129(5): 1375-1383.
130. Giannelli G, Villa E, Lahn M: Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma. Cancer Res. 2014; 74(7): 1890-1894.
131. Zheng X, Gai X, Han S, et al.: The human sulfatase 2 inhibitor 2, 4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer. 2013; 52(3): 225-236.
132. Calvisi DF, Ladu S, Gorden A, et al.: Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006; 130(4): 1117-1128.
133. Yasuda E, Kumada T, Takai S, et al.: Attenuated phosphorylation of heat shock protein 27 correlates with tumor progression in patients with hepatocellular carcinoma. Biochem Biophys Res Commun. 2005; 337(1): 337-342.
134. Burger AM, Seth AK: The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer. 2004; 40(15): 2217-2229.
135. Yang Y, Li CC, Weissman AM: Regulating the p53 system through ubiquitination. Oncogene. 2004; 23(11): 2096-2106.
136. Zhang Y, Chang C, Gehling DJ, et al.: Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci U S A. 2001; 98(3): 974-979.
137. Wang F, Denison S, Lai JP, et al.: Parkin gene alterations in hepatocellular carcinoma. Genes Chromosomes Cancer. 2004; 40(2): 85-96.
138. Yu P, Fu YX: Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest. 2006; 86(3): 231-245.
139. Zhao HQ, Li WM, Lu ZQ, et al.: Roles of Tregs in development of hepatocellular carcinoma: a meta-analysis. World J Gastroenterol. 2014; 20(24): 7971-7978.
140. Budhu A, Forgues M, Ye QH, et al.: Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006; 10(2): 99-111.
141. Hattori E, Okumoto K, Adachi T, et al.: Possible contribution of circulating interleukin-10 (IL-10) to anti-tumor immunity and prognosis in patients with unresectable hepatocellular carcinoma. Hepatol Res. 2003; 27(4): 309-314.
142. Chan SL, Mo FK, Wong CS, et al.: A study of circulating interleukin 10 in prognostication of unresectable hepatocellular carcinoma. Cancer. 2012; 118(16): 3984-3992.
143. Wu K, Kryczek I, Chen L, et al.: Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 2009; 69(20): 8067-8075.
144. Shi F, Shi M, Zeng Z, et al.: PD-1 and PD-L1 upregulation promotes CD8+ T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer. 2011; 128(4): 887-896.
145. El-Khoueiry AB, Melero I, Crocenzi TS, et al.: Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol. 2015; 33(18): (suppl, abstr LBA101).
146. Yamashita T, Wang XW: Cancer stem cells in the development of liver cancer. J Clin Invest. 2013; 123(5): 1911-1918.
147. Marquardt JU, Factor VM, Thorgeirsson SS: Epigenetic regulation of cancer stem cells in liver cancer: current concepts and clinical implications. J Hepatol. 2010; 53(3): 568-577.
148. Song W, Li H, Tao K, et al.: Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract. 2008; 62(8): 1212-1218.
149. Won C, Kim BH, Yi EH, et al.: Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma. Hepatology. 2015; 62(4): 1160-1173.
150. Lee TK, Castilho A, Cheung VC, et al.: CD24+ liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 2011; 9(1): 50-63.