Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 141 No. 4344 (2011)

The parallel universe: microRNAs and their role in chronic hepatitis, liver tissue damage and hepatocarcinogenesis

  • J Haybaeck
  • N Zeller
Cite this as:
Swiss Med Wkly. 2011;141:w13287


In recent years, enormous progress has been made in identifying microRNAs (miRNAs) as important regulators of gene expression and their association with or control of various liver diseases such as fibrosis, hepatitis and hepatocellular carcinoma (HCC). Indeed, many genes encoding miRNAs as well as their targets have been described and their direct or indirect link to the respective liver diseases has been investigated in various experimental systems as well as in human tissue. Here we discuss current knowledge of miRNAs and their involvement in liver diseases, elaborating in particular on the contribution of miRNAs to hepatitis, fibrosis and HCC formation. We also debate possible prognostic, predictive and therapeutic values of respective miRNAs in liver diseases. The discovery of liver disease related miRNAs has constituted a major breakthrough in liver research and will most likely be of high relevance for future therapeutic strategies, especially when dealing with hepatitis, fibrosis and HCC.


  1. Friedman JM, Jones PA. Micrornas: Critical mediators of differentiation, development and disease. Swiss Med Wkly. 2009;139:466–72.
  2. Lee RC, Feinbaum RL, Ambros V. The c. Elegans heterochronic gene lin-4 encodes small rnas with antisense complementarity to lin-14. Cell. 1993;75:843–54.
  3. Boutz DR, Collins P, Suresh U, Lu M, Ramirez CM, Fernandez-Hernando C, et al. A two-tiered approach identifies a network of cancer and liver diseases related genes regulated by mir-122. J Biol Chem.
  4. Davis-Dusenbery BN, Hata A. Mechanisms of control of microrna biogenesis. J Biochem. 148:381–92.
  5. Li Y, He C, Jin P. Emergence of chemical biology approaches to the rnai/mirna pathway. Chem Biol. 17:584–9.
  6. Deiters A. Small molecule modifiers of the microrna and rna interference pathway. AAPS J. 12:51–60.
  7. Li C, Feng Y, Coukos G, Zhang L. Therapeutic microrna strategies in human cancer. AAPS J. 2009;11:747–57.
  8. Steitz JA, Vasudevan S. Mirnps: Versatile regulators of gene expression in vertebrate cells. Biochem Soc Trans. 2009;37:931–5.
  9. Eulalio A, Huntzinger E, Izaurralde E. Getting to the root of mirna-mediated gene silencing. Cell. 2008;132:9–14.
  10. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific micrornas from mouse. Curr Biol. 2002;12:735–9.
  11. Triboulet R, Gregory RI. Autoregulatory mechanisms controlling the microprocessor. Adv Exp Med Biol. 700:56–66.
  12. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear rnase iii drosha initiates microrna processing. Nature. 2003;425:415–9.
  13. Ge Q, Ilves H, Dallas A, Kumar P, Shorenstein J, Kazakov SA, Johnston BH. Minimal-length short hairpin rnas: The relationship of structure and rnai activity. RNA. 16:106–17.
  14. Zucman-Rossi J. Molecular classification of hepatocellular carcinoma. Dig Liver Dis. 42(Suppl 3):S235–241.
  15. Kwak PB, Iwasaki S, Tomari Y. The microrna pathway and cancer. Cancer Sci. 101:2309–15.
  16. Pratt AJ, MacRae IJ. The rna-induced silencing complex: A versatile gene-silencing machine. J Biol Chem. 2009;284:17897–901.
  17. Ameres SL, Martinez J, Schroeder R. Molecular basis for target rna recognition and cleavage by human risc. Cell. 2007;130:101–12.
  18. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Expression profiling of mammalian micrornas uncovers a subset of brain-expressed micrornas with possible roles in murine and human neuronal differentiation. Genome Biol. 2004;5:R13.
  19. Qiao C, Yuan Z, Li J, He B, Zheng H, Mayer C, Xiao X. Liver-specific microrna-122 target sequences incorporated in aav vectors efficiently inhibits transgene expression in the liver. Gene Ther. 18:403–10.
  20. Law PT, Wong N. Emerging roles of microrna in the intracellular signaling networks of hepatocellular carcinoma. J Gastroenterol Hepatol. 26:437–49.
  21. Panarelli NC, Yantiss RK. Microrna expression in selected carcinomas of the gastrointestinal tract. Patholog Res Int. 2011:124608.
  22. Tanaka S, Arii S. Molecularly targeted therapy for hepatocellular carcinoma. Cancer Sci. 2009;100:1–8.
  23. Schwiegk H. Physiology and functional pathology of the circulation of the liver. Dtsch Z Verdau Stoffwechselkr. 1953;9:85–104.
  24. Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol. 1992;54:885–909.
  25. Strange RC. Hepatic bile flow. Physiol Rev. 1984;64:1055–102.
  26. Zhang G, Wang Q, Xu R. Therapeutics based on microrna: A new approach for liver cancer. Curr Genomics. 11:311–25.
  27. Henke JI, Goergen D, Zheng J, Song Y, Schuttler CG, Fehr C, et al. Microrna-122 stimulates translation of hepatitis c virus rna. EMBO J. 2008;27:3300–10.
  28. Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, et al. Widespread microrna repression by myc contributes to tumorigenesis. Nat Genet. 2008;40:43–50.
  29. Li Y, Jiang Z, Xu L, Yao H, Guo J, Ding X. Stability analysis of liver cancer-related micrornas. Acta Biochim Biophys Sin. (Shanghai);43:69–78.
  30. Charette N, Leclercq IA. Why should the gastroenterologist bother about obesity? An oncologic point of view. Acta Gastroenterol Belg. 73:504–9.
  31. Chavez-Tapia NC, Rosso N, Tiribelli C. In vitro models for the study of non-alcoholic fatty liver disease. Curr Med Chem. 18:1079–84.
  32. Ferland-McCollough D, Ozanne SE, Siddle K, Willis AE, Bushell M. The involvement of micrornas in type 2 diabetes. Biochem Soc Trans. 38:1565–70.
  33. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, et al. Silencing of micrornas in vivo with “antagomirs”. Nature. 2005;438:685–9.
  34. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, et al. Mir-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3:87–98.
  35. Filipowicz W, Grosshans H. The liver-specific microrna mir-122: Biology and therapeutic potential. Prog Drug Res. 67:221–38.
  36. Boursier J, Louvet A. Liver fibrogenesis and genetic factors. Clin Res Hepatol Gastroenterol. 35(Suppl 1):S3–9.
  37. Anty R, Lemoine M. Liver fibrogenesis and metabolic factors. Clin Res Hepatol Gastroenterol. 35(Suppl 1):S10–20.
  38. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18.
  39. Sekiya Y, Ogawa T, Iizuka M, Yoshizato K, Ikeda K, Kawada N. Down-regulation of cyclin e1 expression by microrna-195 accounts for interferon-beta-induced inhibition of hepatic stellate cell proliferation. J Cell Physiol.
  40. Moroy T, Geisen C. Cyclin e. Int J Biochem Cell Biol. 2004;36:1424–39.
  41. Geyer CR. Strategies to re-express epigenetically silenced p15(ink4b) and p21(waf1) genes in acute myeloid leukemia. Epigenetics. 5:696–703.
  42. Roderburg C, Urban GW, Bettermann K, Vucur M, Zimmermann H, Schmidt S, et al. Micro-rna profiling reveals a role for mir-29 in human and murine liver fibrosis. Hepatology. 53:209–18.
  43. Chau BN, Brenner DA. What goes up must come down: The emerging role of microrna in fibrosis. Hepatology. 53:4–6.
  44. Yuan B, Dong R, Shi D, Zhou Y, Zhao Y, Miao M, et al. Down-regulation of mir-23b may contribute to activation of the tgf-beta1/smad3 signalling pathway during the termination stage of liver regeneration. FEBS Lett. 585:927–34.
  45. Nagata H, Hatano E, Tada M, Murata M, Kitamura K, Asechi H, et al. Inhibition of c-jun nh2-terminal kinase switches smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma. Hepatology. 2009;49:1944–53.
  46. Mei Y, Thevananther S. Endothelial nitric oxide synthase is a key mediator of hepatocyte proliferation in response to partial hepatectomy in mice. Hepatology.
  47. Chen X, Murad M, Cui YY, Yao LJ, Venugopal SK, Dawson K, et al. Mirna regulation of liver growth after 50% partial hepatectomy and small size grafts in rats. Transplantation. 91:293–9.
  48. Verna L, Whysner J, Williams GM. N-nitrosodiethylamine mechanistic data and risk assessment: Bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther. 1996;71:57–81.
  49. Li WQ, Chen C, Xu MD, Guo J, Li YM, Xia QM, et al. The rno-mir-34 family is upregulated and targets acsl1 in dimethylnitrosamine-induced hepatic fibrosis in rats. FEBS J.
  50. Yang N, Mahato RI. Gfap promoter-driven rna interference on tgf-beta1 to treat liver fibrosis. Pharm Res. 28:752–61.
  51. Murakami Y, Toyoda H, Tanaka M, Kuroda M, Harada Y, Matsuda F, et al. The progression of liver fibrosis is related with overexpression of the mir-199 and 200 families. PLoS One. 6:e16081.
  52. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.
  53. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability. Carcinogenesis. 2009;30:1073–81.
  54. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 144:646–74.
  55. Ben-David U, Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer. 11:268–77.
  56. Kim N, Kim H, Jung I, Kim Y, Kim D, Han YM. Expression profiles of mirnas in human embryonic stem cells during hepatocyte differentiation. Hepatol Res. 41:170–83.
  57. Li R, Qian N, Tao K, You N, Wang X, Dou K. Micrornas involved in neoplastic transformation of liver cancer stem cells. J Exp Clin Cancer Res. 29:169.
  58. Cairo S, Wang Y, de Reynies A, Duroure K, Dahan J, Redon MJ, et al. Stem cell-like micro-rna signature driven by myc in aggressive liver cancer. Proc Natl Acad Sci U S A;107:20471–6.
  59. Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A, et al. Mir-130b promotes cd133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell. 7:694–707.
  60. Albulescu R, Neagu M, Albulescu L, Tanase C. Tissular and soluble mirnas for diagnostic and therapy improvement in digestive tract cancers. Expert Rev Mol Diagn. 11:101–20.
  61. von Frowein J, Pagel P, Kappler R, von Schweinitz D, Roscher A, Schmid I. Microrna-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma. Hepatology. 53:833–42.
  62. Meng XZ, Zheng TS, Chen X, Wang JB, Zhang WH, Pan SH, et al. Microrna expression alteration after arsenic trioxide treatment in hepg-2 cells. J Gastroenterol Hepatol. 26:186–93.
  63. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both raf and vegf and pdgf receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40.
  64. Fernando J, Sancho P, Fernandez-Rodriguez CM, Lledo JL, Caja L, Campbell J, et al. Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli. J Cell Physiol.
  65. Sharma AD, Narain N, Handel EM, Iken M, Singhal N, Cathomen T, et al. Microrna-221 regulates fas-induced fulminant liver failure. Hepatology.
  66. Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. Mir-221 controls cdkn1c/p57 and cdkn1b/p27 expression in human hepatocellular carcinoma. Oncogene. 2008;27:5651–61.
  67. Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B, et al. Mir-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci. U S A;107:264–9.
  68. Schmittgen TD. Mir-31: A master regulator of metastasis? Future Oncol. 6:17–20.
  69. Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, et al. Identification of microrna-181 by genome-wide screening as a critical player in epcam-positive hepatic cancer stem cells. Hepatology. 2009;50:472–80.
  70. Yang F, Yin Y, Wang F, Wang Y, Zhang L, Tang Y, et al. Mir-17-5p promotes migration of human hepatocellular carcinoma cells through the p38 mitogen-activated protein kinase-heat shock protein 27 pathway. Hepatology. 51:1614–23.
  71. Wang B, Hsu SH, Majumder S, Kutay H, Huang W, Jacob ST, et al. Tgfbeta-mediated upregulation of hepatic mir-181b promotes hepatocarcinogenesis by targeting timp3. Oncogene. 29:1787–97.
  72. Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 2009;16:295–308.
  73. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. Nf-kappab functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–6.
  74. Karin M. Inflammation and cancer: The long reach of ras. Nat Med. 2005;11:20–1.
  75. Karin M, Greten FR. Nf-kappab: Linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749–59.
  76. Mizuguchi Y, Mishima T, Yokomuro S, Arima Y, Kawahigashi Y, Shigehara K, et al. Sequencing and bioinformatics-based analyses of the microrna transcriptome in hepatitis b-related hepatocellular carcinoma. PLoS One. 6:e15304.
  77. Wu FL, Jin WB, Li JH, Guo AG. Targets for human encoded micrornas in hbv genes. Virus Genes.
  78. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis c virus rna abundance by a liver-specific microrna. Science. 2005;309:1577–81.
  79. Sarasin-Filipowicz M, Krol J, Markiewicz I, Heim MH, Filipowicz W. Decreased levels of microrna mir-122 in individuals with hepatitis c responding poorly to interferon therapy. Nat Med. 2009;15:31–3.
  80. Vazquez-Del Mercado M, Sanchez-Orozco LV, Pauley BA, Chan JY, Chan EK, Panduro A, et al. Autoantibodies to a mirna-binding protein argonaute2 (su antigen) in patients with hepatitis c virus infection. Clin Exp Rheumatol. 28:842–8.
  81. Roberts AP, Lewis AP, Jopling CL. Mir-122 activates hepatitis c virus translation by a specialized mechanism requiring particular rna components. Nucleic Acids Res.
  82. Ma X, Becker Buscaglia LE, Barker JR, Li Y. Micrornas in nf-{kappa}b signaling. J Mol Cell Biol. 3:159–66.
  83. Sekine S, Ogawa R, Ito R, Hiraoka N, McManus MT, Kanai Y, et al. Disruption of dicer1 induces dysregulated fetal gene expression and promotes hepatocarcinogenesis. Gastroenterology. 2009;136:2304–15.
  84. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer-the stable evidence. Nat Rev Clin Oncol. 7:153–62.
  85. Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene. 2006;25:3778–86.
  86. Nelson KM, Weiss GJ. Micrornas and cancer: Past, present, and potential future. Mol Cancer Ther. 2008;7:3655–60.
  87. Pan Y, Balazs L, Tigyi G, Yue J. Conditional deletion of dicer in vascular smooth muscle cells leads to the developmental delay and embryonic mortality. Biochem Biophys Res Commun. 408:369–74.
  88. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. Microrna expression profiles classify human cancers. Nature. 2005;435:834–8.
  89. Huang YS, Dai Y, Yu XF, Bao SY, Yin YB, Tang M, Hu CX. Microarray analysis of microrna expression in hepatocellular carcinoma and non-tumorous tissues without viral hepatitis. J Gastroenterol Hepatol. 2008;23:87–94.
  90. Huang S, He X. The role of micrornas in liver cancer progression. Br J Cancer. 104:235–40.
  91. Sato F, Hatano E, Kitamura K, Myomoto A, Fujiwara T, Takizawa S, et al. Microrna profile predicts recurrence after resection in patients with hepatocellular carcinoma within the milan criteria. PLoS One;6:e16435.
  92. Gao P, Wong CC, Tung EK, Lee JM, Wong CM, Ng IO. Deregulation of microrna expression occurs early and accumulates in early stages of hbv-associated multistep hepatocarcinogenesis. J Hepatol.
  93. Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, Lee J, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW: Microrna expression, survival, and response to interferon in liver cancer. N Engl J Med 2009;361:1437-1447.
  94. Brase JC, Wuttig D, Kuner R, Sultmann H: Serum micrornas as non-invasive biomarkers for cancer. Mol Cancer;9:306.
  95. Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, et al. Circulating micrornas, mir-21, mir-122, and mir-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog. 50:136–42.
  96. Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M. Circulating micrornas as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol. 45:355–60.
  97. Li XD, Li ZG, Song XX, Liu CF. A variant in microrna-196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology. 42:669–73.
  98. Cawood R, Wong SL, Di Y, Baban DF, Seymour LW. Microrna controlled adenovirus mediates anti-cancer efficacy without affecting endogenous microrna activity. PLoS One;6:e16152.
  99. Liu WH, Yeh SH, Lu CC, Yu SL, Chen HY, Lin CY, et al. Microrna-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology. 2009;136:683–93.
  100. Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, et al. Microrna-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of stathmin1. Gastroenterology. 2008;135:257–69.
  101. Li W, Xie L, He X, Li J, Tu K, Wei L, et al. Diagnostic and prognostic implications of micrornas in human hepatocellular carcinoma. Int J Cancer. 2008;123:1616–22.
  102. Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T, et al. Comprehensive analysis of microrna expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006;25:2537–45.
  103. Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, et al. Association of microrna expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res. 2008;14:419–27.
  104. Li Y, Tan W, Neo TW, Aung MO, Wasser S, Lim SG, et al. Role of the mir-106b-25 microrna cluster in hepatocellular carcinoma. Cancer Sci. 2009;100:1234–42.
  105. Su H, Yang JR, Xu T, Huang J, Xu L, Yuan Y, et al. Microrna-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 2009;69:1135–42.
  106. Connolly E, Melegari M, Landgraf P, Tchaikovskaya T, Tennant BC, Slagle BL, et al. Elevated expression of the mir-17-92 polycistron and mir-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. Am J Pathol. 2008;173:856–64.
  107. Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, et al. Microrna profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008;47:1955–63.
  108. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. Microrna-21 regulates expression of the pten tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133:647–58.
  109. Li S, Fu H, Wang Y, Tie Y, Xing R, Zhu J, et al. Microrna-101 regulates expression of the v-fos fbj murine osteosarcoma viral oncogene homolog (fos) oncogene in human hepatocellular carcinoma. Hepatology. 2009;49:1194–202.
  110. Wang Y, Lee AT, Ma JZ, Wang J, Ren J, Yang Y, et al. Profiling microrna expression in hepatocellular carcinoma reveals microrna-224 up-regulation and apoptosis inhibitor-5 as a microrna-224-specific target. J Biol Chem. 2008;283:13205–15.
  111. Yao J, Liang L, Huang S, Ding J, Tan N, Zhao Y, et al. Microrna-30d promotes tumor invasion and metastasis by targeting galphai2 in hepatocellular carcinoma. Hepatology. 51:846–56.
  112. Wong QW, Ching AK, Chan AW, Choy KW, To KF, Lai PB, et al. Mir-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing akt signaling. Clin Cancer Res. 16:867–75.
  113. Shah YM, Morimura K, Yang Q, Tanabe T, Takagi M, Gonzalez FJ. Peroxisome proliferator-activated receptor alpha regulates a microrna-mediated signaling cascade responsible for hepatocellular proliferation. Mol Cell Biol. 2007;27:4238–47.
  114. Zhang X, Liu S, Hu T, He Y, Sun S. Up-regulated microrna-143 transcribed by nuclear factor kappa b enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology. 2009;50:490–9.
  115. Ding J, Huang S, Wu S, Zhao Y, Liang L, Yan M, et al. Gain of mir-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating rhogdia. Nat Cell Biol. 12:390–9.
  116. Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A, et al. Identification of metastasis-related micrornas in hepatocellular carcinoma. Hepatology. 2008;47:897–907.
  117. Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, et al. Mir-221&222 regulate trail resistance and enhance tumorigenicity through pten and timp3 downregulation. Cancer Cell. 2009;16:498–509.
  118. Gramantieri L, Fornari F, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. Microrna-221 targets bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res. 2009;15:5073–81.
  119. Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, et al. Cyclin g1 is a target of mir-122a, a microrna frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 2007;67:6092–9.
  120. Yang L, Ma Z, Wang D, Zhao W, Chen L, Wang G. Microrna-602 regulating tumor suppressive gene rassf1a is overexpressed in hepatitis b virus-infected liver and hepatocellular carcinoma. Cancer Biol Ther. 9:803–8.
  121. Datta J, Kutay H, Nasser MW, Nuovo GJ, Wang B, Majumder S, et al. Methylation mediated silencing of microrna-1 gene and its role in hepatocellular carcinogenesis. Cancer Res. 2008;68:5049–58.
  122. Lan FF, Wang H, Chen YC, Chan CY, Ng SS, Li K, et al. Hsa-let-7g inhibits proliferation of hepatocellular carcinoma cells by downregulation of c-myc and upregulation of p16(ink4a). Int J Cancer. 128:319–31.
  123. Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, et al. The let-7 family of micrornas inhibits bcl-xl expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol. 52:698–704.
  124. Ji J, Zhao L, Budhu A, Forgues M, Jia HL, Qin LX, et al. Let-7g targets collagen type i alpha2 and inhibits cell migration in hepatocellular carcinoma. J Hepatol. 52:690–7.
  125. Salvi A, Sabelli C, Moncini S, Venturin M, Arici B, Riva P, Portolani N, et al. Microrna-23b mediates urokinase and c-met downmodulation and a decreased migration of human hepatocellular carcinoma cells. FEBS J. 2009;276:2966–82.
  126. Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, et al. Therapeutic microrna delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005–17.
  127. Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, et al. Effects of microrna-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology. 51:836–45.
  128. Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, et al. Microrna-122, a tumor suppressor microrna that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology. 2009;49:1571–82.
  129. Bai S, Nasser MW, Wang B, Hsu SH, Datta J, Kutay H, et al. Microrna-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem. 2009;284:32015–27.
  130. Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS. Loss of mir-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene. 2009;28:3526–36.
  131. Ma L, Liu J, Shen J, Liu L, Wu J, Li W, et al. Expression of mir-122 mediated by adenoviral vector induces apoptosis and cell cycle arrest of cancer cells. Cancer Biol Ther. 9:554–61.
  132. Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I, Inazawa J. Mir-124 and mir-203 are epigenetically silenced tumor-suppressive micrornas in hepatocellular carcinoma. Carcinogenesis. 31:766–76.
  133. Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R, et al. Differential microrna expression between hepatitis b and hepatitis c leading disease progression to hepatocellular carcinoma. Hepatology. 2009;49:1098–112.
  134. Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S, et al. Mir-122/cyclin g1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2009;69:5761–7.
  135. Xu T, Zhu Y, Xiong Y, Ge YY, Yun JP, Zhuang SM. Microrna-195 suppresses tumorigenicity and regulates g1/s transition of human hepatocellular carcinoma cells. Hepatology. 2009;50:113–21.
  136. Liu AM, Poon RT, Luk JM. Microrna-375 targets hippo-signaling effector yap in liver cancer and inhibits tumor properties. Biochem Biophys Res Commun. 394:623–7.