The genetic and epigenetic alterations in human hepatocellular carcinoma: a recent update

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally accepted that the progression of HCC is a long-term process with accumulation of multiple genetic and epigenetic alterations, which further lead to the activation of critical oncogenes or inactivation of tumor suppressor genes. HCC is characterized with multiple cancer hallmarks including their ability to proliferate, anti-apoptosis, invade, metastasis, as well as the emerging features such as stem cell properties and energy metabolic switch. The irreversible alterations at genetic level could be detected as early as in the pre-neoplastic stages and accumulate during cancer progression. Thus, they might account for the cancer initiating steps and further malignant transformation. In addition to genetic alterations, epigenetic alterations can affect the cancer transcriptome more extensively. Alterations in DNA methylation, histone modification, miRNAs, RNA editing, and lncRNAs might result in disrupted gene regulation networks and substantially contribute to HCC progression. In this review, the genetic and epigenetic alterations which significantly contribute to the malignant capabilities of HCC will be updated and summarized in detail. Further characterization of those critical molecular events might better elucidate the pathogenesis of HCC and provide novel therapeutic targets for treatment of this deadly disease.

Key words： hepatocellular carcinoma (HCC); cancer hallmarks; genetic regulation; epigenetic regulation; therapeutic targets; HCC progression

References

1 Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene26: 1324-1337

2 Antoniou AC, Beesley J, McGuffog L, Sinilnikova OM, Healey S, Neuhausen SL, Ding YC, Rebbeck TR, Weitzel JN, Lynch HT (2010) Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res70: 9742-9754

3 Arii S, Mise M, Harada M, Furutani M, Ishigami S, Niwano M, Mizumoto M, Fukumoto M, Imamura M (1996) Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology24: 316-322

4 Armeanu S, Pathil A, Venturelli S, Mascagni P, Weiss TS, Gottlicher M, Gregor M, Lauer UM, Bitzer M (2005) Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylase inhibitors valproate and ITF2357. J Hepatol42: 210-217

5 Athanasiadis A, Rich A, Maas S (2004) Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol2: e391

6 Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A, Weinberg RA (2008) An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet40: 499-507

7 Beyoglu D, Imbeaud S, Maurhofer O, Bioulac-Sage P, Zucman-Rossi J, Dufour JF, Idle JR (2013) Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classiflcation. Hepatology58: 229-238

8 Bingle L, Brown NJ, Lewis CE (2002) The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol196: 254-265

9 Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, Zanetti KA, Ye QH, Qin LX, Croce CM (2008) Identiflcation of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology47: 897-907

10 Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer11: 85-95

11 Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA, Schroeder I, Factor VM, Thorgeirsson SS (2007) Mechanistic and prognostic signiflcance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. J Clin Invest117: 2713-2722

12 Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature407: 249-257

13 Cavallaro U, Christofori G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer4: 118-132

14 Chan THM, Chen LL, Liu M, Hu L, Zheng BJ, Poon VKM, Huang PZ, Yuan YF, Huang JD, Yang J (2012) Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development. Hepatology55: 491-505

15 Chan TH, Lin CH, Qi L, Fei J, Li Y, Yong KJ, Liu M, Song Y, Chow RK, Ng VH (2013) A disrupted RNA editing balance mediated by ADARs (adenosine deaminases that act on RNA) in human hepatocellular carcinoma. Gut63(5): 832-843

16 Chang Y, Yan W, He XX, Zhang LM, Li CJ, Huang H, Nace G, Geller DA, Lin JS, Tsung A (2012) miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology143: 177.e8-187.e8

17 Chen YC, Lin MC, Yao H, Wang H, Zhang AQ, Yu J, Hui CK, Lau GK, He ML, Sung J (2007) Lentivirus-mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin (vol. 46, p. 200, 2007). Hepatology46: 1314

18 Chen LL, Hu L, Chan THM, Tsao GSW, Xie D, Huo KK, Fu L, Ma S, Zheng BJ, Guan XY (2009a) Chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L) gene suppresses the nucleus-to-mitochondria translocation of Nur77 to sustain hepatocellular carcinoma cell survival. Hepatology50: 122-129

19 Chen MH, Huang JD, Hu L, Zheng BJ, Chen LL, Tsang SL, Guan XY (2009b) Transgenic CHD1L expression in mouse induces spontaneous tumors. PLoS One4(8): e6727

20 Chen LL, Chan THM, Yuan YF, Hu L, Huang J, Ma S, Wang J, Dong SS, Tang KH, Xie D (2010) CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients. J Clin Invest120: 1178-1191

21 Chen LL, Yuan YF, Li Y, Chan THM, Zheng BJ, Huang J, Guan XY (2011) Clinical signiflcance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion. Gut60: 534-543

22 Chen LL, Li Y, Lin CH, Chan THM, Chow RKK, Song YY, Liu M, Yuan YF, Fu L, Kong KL (2013) Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med19: 209-216

23 Chochi Y, Kawauchi S, Nakao M, Furuya T, Hashimoto K, Oga A, Oka M, Sasaki K (2009) A copy number gain of the 6p arm is linked with advanced hepatocellular carcinoma: an array-based comparative genomic hybridization study. J Pathol217: 677-684

24 Colombino M, Sperlongano P, Izzo F, Tatangelo F, Botti G, Lombardi A, Accardo M, Tarantino L, Sordelli I, Agresti M (2012) BRAF and PIK3CA genes are somatically mutated in hepatocellular carcinoma among patients from South Italy. Cell Death Dis3: e259

25 Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S, Liu CG, Volinia S, Croce CM, Schmittgen TD (2008) Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res68: 5049-5058

26 Ding T, Xu J, Wang F, Shi M, Zhang Y, Li SP, Zheng LM (2009) High tumor-inflltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum Pathol40: 381-389

27 Ding J, Huang SL, Wu SQ, Zhao YJ, Liang LH, Yan MX, Ge C, Yao J, Chen TY, Wan DF (2010) Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA. Nat Cell Biol12: 390-399

28 Ding J, Huang SL, Wang Y, Tian Q, Zha RP, Shi HB, Wang QF, Ge C, Chen TY, Zhao YJ (2013) Genome-wide screening reveals that miR-195 targets the TNF-/NF-B pathway by downregulating IB kinase alpha and TAB3 in hepatocellular carcinoma. Hepatology58: 654-666

29 El Tayebi HM, Omar K, Hegy S, El Maghrabi M, El Brolosy M, Hosny KA, Esmat G, Abdelaziz AI (2013) Repression of miR-17-5p with elevated expression of E2F-1 and c-MYC in non-metastatic hepatocellular carcinoma and enhancement of cell growth upon reversing this expression pattern. Biochem Biophys Res Commun434: 421-427

30 El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology132: 2557-2576

31 Endo M, Yasui K, Zen Y, Gen Y, Zen K, Tsuji K, Dohi O, Mitsuyoshi H, Tanaka S, Taniwaki M (2013) Alterations of the SWI/SNF chromatin remodelling subunit-BRG1 and BRM in hepatocellular carcinoma. Liver Int33: 105-117

32 Fang W, Piao Z, Simon D, Sheu JC, Huang S (2000) Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13-p36.23 and mutational analysis of the RIZ (PRDM2) gene localized to the region. Genes chromosomes cancer28: 269-275

33 Farber E (1984) The multistep nature of cancer development. Cancer Res44: 4217-4223

34 Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, Nevens F, Solinas A, Mura D, Brouwer JT (1997) Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology112: 463-472

35 Finn RS, Zhu AX (2009) Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. Expert Rev Anticancer Ther9: 503-509

36 Fiume L, Manerba M, Vettraino M, Di Stefano G (2011) Effect of sorafenib on the energy metabolism of hepatocellular carcinoma cells. Eur J Pharmacol670: 39-43

37 Fodde R, Brabletz T (2007) Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol19: 150-158

38 Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Giovannini C, Croce CM, Bolondi L (2008) MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene27: 5651-5661

39 Fornari F, Milazzo M, Chieco P, Negrini M, Calin GA, Grazi GL, Pollutri D, Croce CM, Bolondi L, Gramantieri L (2010) MiR-199a-3p Regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res70: 5184-5193

40 Fu L, Dong SS, Xie YW, Tai LS, Chen L, Kong KL, Man K, Xie D, Li Y, Cheng Y (2010) Down-regulation of tyrosine aminotransferase at a frequently deleted region 16q22 contributes to the pathogenesis of hepatocellular carcinoma. Hepatology51: 1624-1634

41 Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, Aoki M, Hosono N, Kubo M, Miya F (2012) Whole-genome sequencing of liver cancers identifles etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet44: 760-764

42 Fujiwara Y, Hoon DS, Yamada T, Umeshita K, Gotoh M, Sakon M, Nishisho I, Monden M (2000) PTEN / MMAC1 mutation and frequent loss of heterozygosity identifled in chromosome 10q in a subset of hepatocellular carcinomas. JJpn J Cancer Res91: 287-292

43 Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M, Lupo L, Schiraldi O, Antonaci S (2002) Clinical role of MMP-2/ TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer97: 425-431

44 Gott JM, Emeson RB (2000) Functions and mechanisms of RNA editing. Annu Rev Genet34: 499-531

45 Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, Grazi GL (2007) Cyclin g1 is a target of miR-122a, a microRNA frequently downregulated in human hepatocellular carcinoma. Cancer Res67: 6092-6099

46 Gramantieri L, Fornari F, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Croce CM, Bolondi L, Negrini M (2009) MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res15: 5073-5081

47 Guan XY, Fang Y, Sham JST, Kwong DLW, Zhang YQ, Liang QW, Li HM, Zhou H, Trent JM (2000) Recurrent chromosome alterations in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer29: 110-116

48 Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Ben Maad I, Calderaro J, Bioulac-Sage P, Letexier M, Degos F (2012) Integrated analysis of somatic mutations and focal copynumber changes identifles key genes and pathways in hepatocellular carcinoma. Nat Genet44: 694-698

49 Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature482(7385): 339-346

50 Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Ruegg MA, Hall MN (2012) Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab15: 725-738

51 Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell100: 57-70

52 Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell144: 646-674

53 He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, Li PY, Song YH, Lin JS (2012) MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene31: 3357-3369

54 Hendrich B, Bird A (1998) Identiflcation and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol18: 6538-6547

55 Hengartner MO (2000) The biochemistry of apoptosis. Nature407: 770-776

56 Henry JC, Park JK, Jiang JM, Kim JH, Nagorney DM, Roberts LR, Banerjee S, Schmittgen TD (2010) miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines. Biochem Biophys Res Commun403: 120-125

57 Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM (2013) Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology144: 512-527

58 Higashitsuji H, Itoh K, Nagao T, Dawson S, Nonoguchi K, Kido T, Mayer RJ, Arii S, Fujita J. (2000). Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrinrepeat protein overexpressed in hepatomas. Nat Med6(1): 96-99

59 Hsu PP, Sabatini DM (2008) Cancer cell metabolism: Warburg and beyond. Cell134: 703-707

60 Hu L, Liu M, Chen LL, Chan THM, Wang J, Huo KK, Zheng BJ, Xie D, Guan XY (2012) SCYL1 binding protein 1 promotes the ubiquitin-dependent degradation of Pirh2 and has tumor-suppressive function in the development of hepatocellular carcinoma. Carcinogenesis33: 1581-1588

61 Hussain SP, Schwank J, Staib F, Wang XW, Harris CC (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene26: 2166-2176

62 Iwata N, Yamamoto H, Sasaki S, Itoh F, Suzuki H, Kikuchi T, Kaneto H, Iku S, Ozeki I, Karino Y (2000) Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 sigma gene in human hepatocellular carcinoma. Oncogene19: 5298-5302

63 Jablkowski M, Bocian A, Bialkowska J, Bartkowiak J (2005) A comparative study of P53/MDM2 genes alterations and P53/ MDM2 proteins immunoreactivity in liver cirrhosis and hepatocellular carcinoma. J Exp Clin Cancer Res24: 117-125

64 Ji JF, Yamashita T, Budhu A, Forgues M, Jia HL, Li CL, Deng CX, Wauthier E, Reid LM, Ye QH (2009) Identiflcation of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology50: 472-480

65 Ji J, Zhao L, Budhu A, Forgues M, Jia HL, Qin LX, Ye QH, Yu J, Shi X, Tang ZY (2010) Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma. J Hepatol52: 690-697

66 Jiang DK, Sun JL, Cao GW, Liu Y, Lin DX, Gao YZ, Ren WH, Long XD, Zhang HX, Ma XP (2013) Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus-related hepatocellular carcinoma. Nat Genet45(1): 72-75

67 Joyce JA (2005) Therapeutic targeting of the tumor microenvironment. Cancer Cell7: 513-520

68 Kanai Y, Ushijima S, Hui AM, Ochiai A, Tsuda H, Sakamoto M, Hirohashi S (1997) The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas. Int J Cancer71: 355-359

69 Kanai Y, Hui AM, Sun L, Ushijima S, Sakamoto M, Tsuda H, Hirohashi S (1999) DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis. Hepatology29: 703-709

70 Kim KW, Bae SK, Lee OH, Bae MH, Lee MJ, Park BC (1998) Insulinlike growth factor II induced by hypoxia may contribute to angiogenesis of human hepatocellular carcinoma. Cancer Res58: 348-351

71 Kim TM, Yim SH, Shin SH, Xu HD, Jung YC, Park CK, Choi JY, Park WS, Kwon MS, Fiegler H (2008) Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q. Int J Cancer123: 2808-2815.

72 Kim J, Woo AJ, Chu JL, Snow JW, Fujiwara Y, Kim CG, Cantor AB, Orkin SH (2010) A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell143: 313-324

73 Ko E, Kim SJ, Joh JW, Park CK, Park J, Kim DH (2008) CpG island hypermethylation of SOCS-1 gene is inversely associated with HBV infection in hepatocellular carcinoma. Cancer Lett271: 240-250

74 Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S (2000) Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis - A comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology32: 970-979

75 Kouzarides T (2007) Chromatin modifications and their function. Cell128: 693-705

76 Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell13: 472-482

77 Kubbutat MHG, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature387: 299-303

78 Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, Otsuka M, Tateishi R, Omata M, Nakagawa H (2011) Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet43: 455-458

79 Kuroki T, Fujiwara Y, Nakamori S, Imaoka S, Kanematsu T, Nakamura Y (1995) Evidence for the presence of two tumoursuppressor genes for hepatocellular carcinoma on chromosome 13q. Br J Cancer72: 383-385

80 Lai MC, Yang Z, Zhou L, Zhu QQ, Xie HY, Zhang F, Wu LM, Chen LM, Zheng SS (2012) Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol29: 1810-1816

81 Lang QB, Ling CQ (2012) MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun426: 247-252

82 Law PTY, Ching AKK, Chan AWH, Wong QWL, Wong CK, To KF, Wong N (2012) MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma. Carcinogenesis33: 1134-1141

83 Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH (2003) Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol163: 1371-1378

84 Lee TK, Poon RTP, Yuen AP, Ling MT, Kwok WK, Wang XH, Wong YC, Guan XY, Man K, Chau KL (2006) Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res12: 5369-5376

85 Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO (2011) CD24 (+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell9: 50-63

86 Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell141: 1117-1134

87 Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science330: 1340-1344

88 Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y, Zheng X (2009) miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett275: 44-53

89 Li J, Fu H, Xu C, Tie Y, Xing R, Zhu J, Qin Y, Sun Z, Zheng X (2010) miR-183 inhibits TGF-beta1-induced apoptosis by downregulation of PDCD4 expression in human hepatocellular carcinoma cells. BMC Cancer10: 354

90 Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ (2011) Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet43: 828-829

91 Li SP, Qian J, Yang Y, Zhao WT, Dai JC, Bei JX, Foo JN, McLaren PJ, Li ZQ, Yang JM (2012) GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers. PLoS Genet8(7): e1002791

92 Li CF, Wang YZ, Wang SF, Wu B, Hao JL, Fan HX, Ju Y, Ding YP, Chen LZ, Chu XY (2013a) Hepatitis B virus mRNA-mediated miR-122 inhibition upregulates PTTG1-binding protein, which promotes hepatocellular carcinoma tumor growth and cell invasion. J Virol87: 2193-2205

93 Li Y, Chen LL, Chan THM, Guan XY (2013b) Hepatocellular carcinoma: transcriptome diversity regulated by RNA editing. Int J Biochem Cell B45: 1843-1848

94 Li J, Quan H, Liu Q, Si Z, He Z, Qi H (2013c) Alterations of axis inhibition protein 1 (AXIN1) in hepatitis B virus-related hepatocellular carcinoma and overexpression of AXIN1 induces apoptosis in hepatocellular cancer cells. Oncol Res20: 281-288

95 Liu WH, Yeh SOH, Lu CC, Yu SL, Chen HY, Lin CY, Chen DS, Chen PJ (2009) MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology136: 683-693

96 Liu AM, Poon RTP, Luk JM (2010) MicroRNA-375 targets Hipposignaling effector YAP in liver cancer and inhibits tumor properties. Biochem Biophys Res Commun394: 623-627

97 Liu M, Chen LL, Chan THM, Wang J, Li Y, Li Y, Zeng TT, Yuan YF, Guan XY (2012) Serum and glucocorticoid kinase 3 at 8q13.1 promotes cell proliferation and survival in hepatocellular carcinoma. Hepatology55: 1754-1765

98 Liu L, Dai Y, Chen J, Zeng T, Li Y, Chen L, Zhu YH, Li J, Xie D, Yuan YF (2013) Maelstrom promotes hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition via Akt/ GSK-3beta/snail signaling. Hepatology59(2): 531-543

99 Liu M, Li Y, Chen L, Chan THM, Song Y, Fu L, Zeng TT, Dai YD, Zhu YH, Li Y (2014) Allele-speciflc imbalance of oxidative stressinduced growth inhibitor 1 associates with progression of hepatocellular carcinoma. Gastroenterology146(4): 1084-1096

100 Luedde T (2010) MicroRNA-151 and its hosting gene FAK (focal adhesion kinase) regulate tumor cell migration and spreading of hepatocellular carcinoma. Hepatology52: 1164-1166

101 Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ, Guan XY (2007) Identiflcation and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology132: 2542-2556

102 Ma NF, Hu L, Fung JM, Xie D, Zheng BJ, Chen LL, Tang DJ, Fu L, Wu Z, Chen M (2008) Isolation and characterization of a novel oncogene, amplifled in liver cancer 1, within a commonly amplifled region at 1q21 in hepatocellular carcinoma. Hepatology47: 503-510

103 Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A, Ng I, Man K, Wong N, To KF (2010) miR-130b promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell7: 694-707

104 Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I, Geller D, Lee YH, Kitade M, Holczbauer A, Gillen MC (2011) Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology54: 1031-1042

105 Meng FY, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology133: 647-658

106 Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet10: 155-159

107 Merle P, De La Monte S, Kim M, Herrmann M, Tanaka S, Von dem Bussche A, Kew MC, Trepo C, Wands JR (2004) Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology127: 1110-1122

108 Mise M, Arii S, Higashituji H, Furutani M, Niwano M, Harada T, Ishigami SI, Toda Y, Nakayama H, Fukumoto M (1996) Clinical signiflcance of vascular endothelial growth factor and basic flbroblast growth factor gene expression in liver turner. Hepatology23: 455-464

109 Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, Johnson L, Reddy EP (2009) Liver stem cells and hepatocellular carcinoma. Hepatology49: 318-329

110 Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimano T, Nakamura Y (1998) Activation of the betacatenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res58: 2524-2527

111 Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y, Sasaki H (2001) Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood97: 1172-1179

112 Momparler RL (2003) Cancer epigenetics. Oncogene22: 6479-6483

113 Murakami Y, Tamori A, Itami S, Tanahashi T, Toyoda H, Tanaka M, Wu WH, Brojigin N, Kaneoka Y, Maeda A (2013) The expression level of miR-18b in hepatocellular carcinoma is associated with the grade of malignancy and prognosis. BMC Cancer13: 99

114 Nishida N, Fukuda Y, Kokuryu H, Toguchida J, Yandell DW, Ikenega M, Imura H, Ishizaki K (1993) Role and mutational heterogeneity of the P53-gene in hepatocellular-carcinoma. Cancer Res53: 368-372

115 Nishida N, Fukuda Y, Komeda T, Kita R, Sando T, Furukawa M, Amenomori M, Shibagaki I, Nakao K, Ikenaga M (1994) Ampliflcation and overexpression of the cyclin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res54: 3107-3110

116 Nishimura T, Nishida N, Itoh T, Komeda T, Fukuda Y, Ikai I, Yamaoka Y, Nakao K (2005) Discrete breakpoint mapping and shortest region of overlap of chromosome arm 1q gain and 1p loss in human hepatocellular carcinoma detected by semiquantitative microsatellite analysis. Genes Chromosomes Cancer42: 34-43

117 Noh JH, Chang YG, Kim MG, Jung KH, Kim JK, Bae HJ, Eun JW, Shen Q, Kim SJ, Kwon SH (2013) MiR-145 functions as a tumor suppressor by directly targeting histone deacetylase 2 in liver cancer. Cancer Lett335: 455-462

118 Oh BK, Kim H, Park HJ, Shim YH, Choi J, Park C, Park YN (2007) DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. Int J Mol Med20: 65-73

119 Oka Y, Waterland RA, Killian JK, Nolan CM, Jang HS, Tohara K, Sakaguchi S, Yao T, Iwashita A, Yata Y (2002) M6P/IGF2R tumor suppressor gene mutated in hepatocellular carcinomas in Japan. Hepatology35: 1153-1163

120 Okamoto H, Yasui K, Zhao C, Arii S, Inazawa A (2003) PTK2 and EIF3S3 genes may be ampliflcation targets at 8q23-q24 and are associated with large hepatocellular carcinomas. Hepatology38: 1242-1249

121 Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell99: 247-257

122 Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol2(1): a001008

123 Ozturk M (1991) P53 mutation in hepatocellular-carcinoma after aflatoxin exposure. Lancet338: 1356-1359

124 Parada LA, Hallen M, Tranberg KG, Hagerstrand I, Bondeson L, Mitelman F, Johansson B (1998) Frequent rearrangements of chromosomes 1, 7, and 8 in primary liver cancer. Genes Chromosomes Cancer23: 26-35

125 Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin55: 74-108

126 Pathil A, Armeanu S, Venturelli S, Mascagni P, Weiss TS, Gregor M, Lauer UM, Bitzer M (2006) HDAC inhibitor treatment of hepatoma cells induces both TRAIL-independent apoptosis and restoration of sensitivity to TRAIL. Hepatology43: 425-434

127 Patil MA, Zhang J, Ho C, Cheung ST, Fan ST, Chen X (2006) Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol Ther5: 111-117

128 Pei DQ, Kang TB, Qi HX (2000) Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation. J Biol Chem275: 33988-33997

129 Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature414: 105-111

130 Rousseau B, Menard L, Haurie V, Taras D, Blanc JF, Moreau- Gaudry F, Metzler P, Hugues M, Boyault S, Lemiere S (2007) Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma. Hepatology46: 1108-1118

131 Rundhaug JE (2003) Matrix metalloproteinases, angiogenesis, and cancer—Commentary re: A. C. Lockhart et al., reduction of wound angiogenesis in patients treated with BMS-275291, a broad spectrum matrix metalloproteinase inhibitor. Clin Cancer Res9: 551-554

132 Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H, Ishii H, Hirohashi S (2003) DNA methyltransferase (DNMT) 1 protein expression is signiflcantly increased in human hepatocellular carcinomas with malignant potential and may be a biological predictor of prognosis in hepatocellular carcinoma patients. Hepatology38: 593a-593a

133 Santoni-Rugiu E, Jensen MR, Thorgeirsson SS (1998) Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor alpha. Cancer Res58: 123-134

134 Semela D, Dufour JF (2004) Angiogenesis and hepatocellular carcinoma. J Hepatol41: 864-880

135 Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandl S, Bachmann MH, Borowsky AD, Ruebner B, Cardiff RD (2004) MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature431: 1112-1117

136 Shih TC, Tien YJ, Wen CJ, Yeh TS, Yu MC, Huang CH, Lee YS, Yen TC, Hsieh SY (2012) MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatomaderived growth factor in human hepatoma. J Hepatol57: 584-591

137 Shiraki K, Sugimoto K, Fujikawa K, Yamanaka T, Takase K, Nakano T (2000) Survivin promotes cell proliferation in human hepatocellular carcinoma. Gastroenterology118: A906-A906

138 Song K, Han C, Wu T (2012) Epigenetic regulation of miR-122 expression by PPAR gamma/RXR alpha complex and HBx in hepatocellular carcinoma. Hepatology56: 609a-610a

139 Stamenkovic I (2000) Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol10: 415-433

140 Sudo T, Utsunomiya T, Mimori K, Nagahara H, Ogawa K, Inoue H, Wakiyama S, Fujita H, Shirouzu K, Mori M (2005) Clinicopathological signiflcance of EZH2 mRNA expression in patients with hepatocellular carcinoma. Br J Cancer92: 1754-1758

141 Sugimachi K, Tanaka S, Kameyama T, Taguchi KI, Aishima SI, Shimada M, Sugimachi K, Tsuneyoshi M (2003) Transcriptional repressor snail and progression of human hepatocellular carcinoma. Clin Cancer Res: 2657-2664

142 Takehara T, Liu X, Fujimoto J, Friedman SL, Takahashi H (2001) Expression and role of Bcl-xL in human hepatocellular carcinomas. Hepatology34: 55-61

143 Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet31: 339-346

144 Tsujiuchi T, Sugata E, Masaoka T, Onishi M, Fujii H, Shimizu K, Honoki K (2007) Expression and DNA methylation patterns of Tslc1 and Dal-1 genes in hepatocellular carcinomas induced by N-nitrosodiethylamine in rats. Cancer Sci98: 943-948

145 Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E (1997) Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology25: 619-623

146 Venook AP, Papandreou C, Furuse J, de Guevara LL (2010) The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist15(Suppl 4): 5-13

147 Vertino PM, Sekowski JA, Coll JM, Applegren N, Han S, Hickey RJ, Malkas LH (2002) DNMT1 is a component of a multiprotein DNA replication complex. Cell Cycle1: 416-423

148 Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet9: 138-141

149 Voulgari A, Pintzas A (2009) Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. BBA-Rev Cancer1796: 75-90

150 Wang G, Huang CH, Zhao Y, Cai L, Wang Y, Xiu SJ, Jiang ZW, Yang S, Zhao T, Huang W (2000) Genetic aberration in primary hepatocellular carcinoma: correlation between p53 gene mutation and loss-of-heterozygosity on chromosome 16q21-q23 and 9p21-p23. Cell Res10: 311-323

151 Wang Y, Wu MC, Sham JST, Zhang WG, Wu WQ, Guan XY (2002) Prognostic signiflcance of c-myc and AIB1 ampliflcation in hepatocellular carcinoma—a broad survey using high-throughput tissue microarray. Cancer-Am Cancer Soc95: 2346-2352

152 Wang GG, Allis CD, Chi P (2007a) Chromatin remodeling and cancer, part I: covalent histone modiflcations. Trends Mol Med13: 363-372

153 Wang GG, Allis CD, Chi P (2007b) Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling. Trends Mol Med13: 373-380

154 Wang Y, Lee ATC, Ma JZI, Wang JB, Ren JW, Yang YC, Tantoso E, Li KB, Ooi LLPJ, Tan P (2008) Proflling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-speciflc target. J Biol Chem283: 13205-13215

155 Wang B (2010a) TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene29: 1787-1797

156 Wang Y, Lu YW, Toh ST, Sung WK, Tan P, Chow P, Chung AYF, Jooi LLP, Lee CGL (2010b) Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3. J Hepatol53: 57-66

157 Wang L, Guo ZY, Zhang R, Xin B, Chen R, Zhao J, Wang T, Wen WH, Jia LT, Yao LB (2013a) Pseudogene OCT4-pg4 functions as a natural micro RNA sponge to regulate OCT4 expression by competing for miR-145 in hepatocellular carcinoma. Carcinogenesis34: 1773-1781

158 Wang R, Zhao N, Li S, Fang JH, Chen MX, Yang J, Jia WH, Yuan Y, Zhuang SM (2013b) MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology58: 642-653

159 Wei Y, Van Nhieu JT, Prigent S, Srivatanakul P, Tiollais P, Buendia MA (2002) Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic alterations, beta-catenin expression, and clinical features. Hepatology36: 692-701

160 Whiteside TL (2008) The tumor microenvironment and its role in promoting tumor growth. Oncogene27: 5904-5912

161 Wong CM, Lee JMF, Ching YP, Jin DY, Ng IOL (2003) Genetic and epigenetic alterations of DLC-1 gene in hepatocellular carcinoma. Cancer Res63: 7646-7651

162 Wong QWL, Lung RWM, Law BG, Lai PBS, Chan KYY, To KF, Wong N (2008) MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology135: 257-269

163 Wong CCL, Wong CM, Tung EKK, Au SLK, Lee JMF, Poon RTP, Man K, Ng IOL (2011) The MICRORNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating rho-kinase 2. Gastroenterology140: 322-331

164 Xia HP, Ooi LLPJ, Hui KM (2012) MiR-214 Targets beta-catenin pathway to suppress invasion, stem-like traits and recurrence of human hepatocellular carcinoma. PLoS One7(9): e44206

165 Xiong YJ (2010) Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology51: 836-845

166 Xu T, Zhu Y, Xiong Y, Ge YY, Yun JP, Zhuang SM (2009) MicroRNA- 195 suppresses tumorigenicity and regulates G1/S transition of human hepatocellular carcinoma cells. Hepatology50: 113-121

167 Xu H, He JH, Xiao ZD, Zhang QQ, Chen YQ, Zhou H, Qu LH (2010) Liver-enriched transcription factors regulate microRNA-122 that targetsCUTL1 during liver development. Hepatology52: 1431-1442

168 Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, Zhu Z, Jiao H, Lin J, Jiang K (2013) Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest123: 630-645

169 Yamashita T, Budhu A, Forgues M, Wang XW (2007) Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res67: 10831-10839

170 Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E (2009) EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology136: 1012-1024

171 Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-speciflc growth factors and blood vessel formation. Nature407: 242-248

172 Yang B, Guo MZ, Herman JG, Clark DP (2003) Aberrant promoter methylation proflles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol163: 1101-1107

173 Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, Chu PW, Lam CT, Poon RT, Fan ST (2008) Signiflcance of CD90+ cancer stem cells in human liver cancer. Cancer Cell13: 153-166

174 Yang F, Yin YX, Wang F, Wang YQ, Zhang L, Tang Y, Sun SH (2010) miR-17-5p promotes migration of human hepatocellular carcinoma cells through the P38 mitogen-activated protein kinaseheat shock protein 27 pathway. Hepatology51: 1614-1623

175 Yang F, Zhang L, Huo XS, Yuan JH, Xu D, Yuan SX, Zhu N, Zhou WP, Yang GS, Wang YZ (2011a) Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology54: 1679-1689

176 Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, Zheng SS (2011b) Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol18: 1243-1250

177 Yang X, Liang L, Zhang XF, Jia HL, Qin Y, Zhu XC, Gao XM, Qiao P, Zheng Y, Sheng YY (2013) MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology58: 158-170

178 Yao YJ, Ping XL, Zhang H, Chen FF, Lee PK, Ahsan H, Chen CJ, Lee PH, Pleacocke M, Santella RM (1999) PTEN/MMAC1 mutations in hepatocellular carcinomas. Oncogene18: 3181-3185

179 Yasui K, Arii S, Zhao C, Imoto I, Ueda M, Nagai H, Emi M, Inazawa J (2002) TFDP1, CUL4A, and CDC16 identifled as targets for ampliflcation at 13q34 in hepatocellular carcinomas. Hepatology35: 1476-1484

180 Yau WL, Lam CSC, Ng L, Chow AKM, Chan STC, Chan JYK, Wo JYH, Ng KTP, Man K, Poon RTP (2013) Over-expression of miR-106b promotes cell migration and metastasis in hepatocellular carcinoma by activating epithelial-mesenchymal transition process. PLoS One8(3): e57882

181 Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen YD (2003) Predicting hepatitis B viruspositive metastatic hepatocellular carcinomas using gene expression proflling and supervised machine learning. Nat Med9: 416-423

182 Ying Q, Liang L, Guo W, Zha R, Tian Q, Huang S, Yao J, Ding J, Bao M, Ge C (2011) Hypoxia-inducible microRNA-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma. Hepatology54: 2064-2075

183 Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Huber J, Nakatani T, Tsujinoue H, Yanase K (2002) Synergistic effect of basic flbroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology35: 834-842

184 Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE, Harris CC, Herman JG (2001) SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet28: 29-35

185 Yuan BZ, Miller MJ, Keck CL, Zimonjic DB, Thorgeirsson SS, Popescu NC (1998) Cloning, characterization, and chromosomal localization of a gene frequently deleted in human liver cancer (DLC-1) homologous to rat RhoGAP. Cancer Res58: 2196-2199

186 Yuan F, Zhou W, Zou C, Zhang Z, Hu H, Dai Z, Zhang Y (2010) Expression of Oct4 in HCC and modulation to wnt/beta-catenin and TGF-beta signal p athways. Mol Cell Biochem343: 155-162

187 Yuen MF, Hou JL, Chutaputti A (2009) Hepatocellular carcinoma in the Asia paciflc region. J Gastroenterol Hepatol24: 346-353

188 Yuneva MO, Fan TWM, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T, Mates JM, Alonso FJ, Wang CM, Seo Y (2012) The metabolic proflle of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab15: 157-170

189 Zhang XY, Liu SR, Hu TS, Liu SP, He Y, Sun SH (2009) Up-regulated MicroRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing flbronectin expression. Hepatology50: 490-499

190 Zhang YJ, Ahsan H, Chen Y, Lunn RM, Wang LY, Chen SY, Lee PH, Chen CJ, Santella RM (2002) High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma. Mol Carcinog35: 85-92

191 Zhang HX, Zhai Y, Hu ZB, Wu C, Qian J, Jia WH, Ma FC, Huang WF, Yu LX, Yue W (2010) Genome-wide association study identifles 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet42 (9): 755-758

192 Zhang YZ, Takahashi S, Tasaka A, Yoshima T, Ochi H, Chayama K (2013) Involvement of microRNA-224 in cell proliferation, migration, invasion, and anti-apoptosis in hepatocellular carcinoma. J Gastroenterol Hepatol28: 565-575

193 Zhao XT, Li JJ, He YH, Lan F, Fu LL, Guo JY, Zhao RJ, Ye Y, He M, Chong WM (2001) A novel growth suppressor gene on chromosome 17p13.3 with a high frequency of mutation in human hepatocellular carcinoma. Cancer Res61: 7383-7387

194 Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, Bian XW, Guan XY, Lin MC, Zeng YX (2012) The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut61: 278-289

195 Zheng X, Gai XH, Ding FH, Lu ZT, Tu KS, Yao YM, Liu QG (2013) Histone acetyltransferase PCAF up-regulated cell apoptosis in hepatocellular carcinoma via acetylating histone H4 and inactivating AKT signaling. Mol Cancer12: 96

196 Zhou XL, Thorgeirsson SS, Popescu NC (2004) Restoration of DLC- 1 gene expression induces apoptosis and inhibits both cell growth and tumorigenicity in human hepatocellular carcinoma cells. Oncogene23: 1308-1313

197 Zhou L, Yang ZX, Song WJ, Li QJ, Yang F, Wang DS, Zhang N, Dou KF (2013) MicroRNA-21 regulates the migration and invasion of a stem-like population in hepatocellular carcinoma. Int J Oncol43: 661-669

198 Zhu AX, Duda DG, Sahani DV, Jain RK (2011) HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol8: 292-301

199 Zhu Y, Lu Y, Zhang Q, Liu JJ, Li TJ, Yang JR, Zeng CX, Zhuang SM (2012) MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. Nucleic Acids Res40: 4615-4625

200 Zondervan PE, Wink J, Alers JC, JN IJ, Schalm SW, de Man RA, van Dekken H (2000) Molecular cytogenetic evaluation of virusassociated and non-viral hepatocellular carcinoma: analysis of 26 carcinomas and 12 concurrent dysplasias. J Pathol192: 207-215