Skip to main content

MicroRNAs as Novel Targets in Liver Cancer: Facing the Clinical Challenge

  • Chapter
  • First Online:
MicroRNA Targeted Cancer Therapy
  • 1211 Accesses

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide with a rising incidence in the western world. HCCs are characterized by a phenotypic and molecular heterogeneity that limits therapeutic progress. MicroRNAs play a major role for the pathogenesis and progression of liver cancer. As an essential part of the RNA interference machinery, microRNAs contribute to the regulation of many pro-oncogenic processes in HCC, including proliferation, migration, and survival. Therefore, these epigenetically active small molecules advanced to attractive targets for both diagnosis and therapy of liver cancer. Here, we will try to delineate the role of microRNAs during liver development and disease with a particular focus on the development of HCC. We will further aim to dissect the importance of microRNAs for the regulation of key signaling pathways in liver cancer and discuss the impact of microRNAs for the plasticity and phenotypic characteristics of hepatoma cells as well as for putative liver cancer stem cells. Further, we will review progress in high-throughput technologies as novel tools to identify patterns of deregulated microRNAs for diagnostic and prognostic classification of HCCs and indicate their potential as therapeutic targets. Finally, we will indicate potential conceptual and technological challenges that hamper the progress of microRNA-based treatment strategies in liver cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    Article  PubMed  Google Scholar 

  2. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365(12):1118–1127

    Article  PubMed  CAS  Google Scholar 

  3. Bruix J, Sherman M (2011) American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology 53(3):1020–1022

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bruix J, Boix L, Sala M, Llovet JM (2004) Focus on hepatocellular carcinoma. Cancer Cell 5(3):215–219

    Article  PubMed  CAS  Google Scholar 

  5. Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31:339–346

    Article  PubMed  CAS  Google Scholar 

  6. Zender L, Villanueva A, Tovar V, Sia D, Chiang DY, Llovet JM (2010) Cancer gene discovery in hepatocellular carcinoma. J Hepatol 52(6):921–929

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447(7143):433–440

    Article  PubMed  CAS  Google Scholar 

  8. Ventura A, Jacks T (2009) MicroRNAs and cancer: short RNAs go a long way. Cell 136(4):586–591

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4(2):143–153

    Article  PubMed  CAS  Google Scholar 

  10. Wang XW, Heegaard NH, Orum H (2012) MicroRNAs in liver disease. Gastroenterology 142(7):1431–1443

    Article  PubMed  CAS  Google Scholar 

  11. Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Minguez B, Llovet JM (2010) Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis 30(1):35–51

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S et al (2008) MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology 47(6):1955–1963

    Article  PubMed  CAS  Google Scholar 

  13. Giordano S, Columbano A (2013) MicroRNAs: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma? Hepatology 57(2):840–847

    Article  PubMed  CAS  Google Scholar 

  14. Marquardt JU, Galle PR, Teufel A (2012) Molecular diagnosis and therapy of hepatocellular carcinoma (HCC): an emerging field for advanced technologies. J Hepatol 56(1):267–275

    Article  PubMed  Google Scholar 

  15. Schulte JH, Marschall T, Martin M, Rosenstiel P, Mestdagh P, Schlierf S et al (2010) Deep sequencing reveals differential expression of microRNAs in favorable versus unfavorable neuroblastoma. Nucleic Acids Res 38(17):5919–5928

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Szabo G, Bala S (2013) MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 10(9):542–552

    Article  PubMed  CAS  Google Scholar 

  17. Sekine S, Ogawa R, Ito R, Hiraoka N, McManus MT, Kanai Y (2009) Disruption of Dicer1 induces dysregulated fetal gene expression and promotes hepatocarcinogenesis. Gastroenterology 136(7):2304–2315, e2301–2304

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12(9):735–739

    Article  PubMed  CAS  Google Scholar 

  19. Laudadio I, Manfroid I, Achouri Y, Schmidt D, Wilson MD, Cordi S et al (2012) A feedback loop between the liver-enriched transcription factor network and miR-122 controls hepatocyte differentiation. Gastroenterology 142(1):119–129

    Article  PubMed  CAS  Google Scholar 

  20. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3(2):87–98

    Article  PubMed  CAS  Google Scholar 

  21. Liu D, Fan J, Zeng W, Zhou Y, Ingvarsson S, Chen H (2010) Quantitative analysis of miRNA expression in several developmental stages of human livers. Hepatol Res 40(8):813–822

    Article  PubMed  CAS  Google Scholar 

  22. Hand NJ, Master ZR, Eauclaire SF, Weinblatt DE, Matthews RP, Friedman JR (2009) The microRNA-30 family is required for vertebrate hepatobiliary development. Gastroenterology 136(3):1081–1090

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Chen H, Sun Y, Dong R, Yang S, Pan C, Xiang D et al (2011) Mir-34a is upregulated during liver regeneration in rats and is associated with the suppression of hepatocyte proliferation. PLoS One 6(5):e20238

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Pan C, Chen H, Wang L, Yang S, Fu H, Zheng Y et al (2012) Down-regulation of MiR-127 facilitates hepatocyte proliferation during rat liver regeneration. PLoS One 7(6):e39151

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Shu J, Kren BT, Xia Z, Wong PY, Li L, Hanse EA et al (2011) Genomewide microRNA down-regulation as a negative feedback mechanism in the early phases of liver regeneration. Hepatology 54(2):609–619

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Zhou J, Ju W, Wang D, Wu L, Zhu X, Guo Z et al (2012) Down-regulation of microRNA-26a promotes mouse hepatocyte proliferation during liver regeneration. PLoS One 7(4):e33577

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Song G, Sharma AD, Roll GR, Ng R, Lee AY, Blelloch RH et al (2010) MicroRNAs control hepatocyte proliferation during liver regeneration. Hepatology 51(5):1735–1743

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Ng R, Song G, Roll GR, Frandsen NM, Willenbring H (2012) A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration. J Clin Invest 122(3):1097–1108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM (2013) Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144(3):512–527

    Article  PubMed  PubMed Central  Google Scholar 

  30. Braconi C, Patel T (2008) MicroRNA expression profiling: a molecular tool for defining the phenotype of hepatocellular tumors. Hepatology 47(6):1807–1809

    Article  PubMed  CAS  Google Scholar 

  31. Dolganiuc A, Petrasek J, Kodys K, Catalano D, Mandrekar P, Velayudham A et al (2009) MicroRNA expression profile in Lieber-DeCarli diet-induced alcoholic and methionine choline deficient diet-induced nonalcoholic steatohepatitis models in mice. Alcohol Clin Exp Res 33(10):1704–1710

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Elamin BK, Callegari E, Gramantieri L, Sabbioni S, Negrini M (2011) MicroRNA response to environmental mutagens in liver. Mutat Res 717(1–2):67–76

    Article  PubMed  CAS  Google Scholar 

  33. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309(5740):1577–1581

    Article  PubMed  CAS  Google Scholar 

  34. Marquez RT, Bandyopadhyay S, Wendlandt EB, Keck K, Hoffer BA, Icardi MS et al (2010) Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans. Lab Invest 90(12):1727–1736

    Article  PubMed  CAS  Google Scholar 

  35. Zhang Y, Wei W, Cheng N, Wang K, Li B, Jiang X et al (2012) Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology 56(5):1631–1640

    Article  PubMed  CAS  Google Scholar 

  36. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K et al (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368(18):1685–1694

    Article  PubMed  CAS  Google Scholar 

  37. Wang S, Qiu L, Yan X, Jin W, Wang Y, Chen L et al (2012) Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G(1) -modulated P53 activity. Hepatology 55(3):730–741

    Article  PubMed  CAS  Google Scholar 

  38. Ura S, Honda M, Yamashita T, Ueda T, Takatori H, Nishino R et al (2009) Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma. Hepatology 49(4):1098–1112

    Article  PubMed  CAS  Google Scholar 

  39. Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ et al (2008) Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 14(2):419–427

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Friedman SL (2012) Liver fibrosis in 2012: convergent pathways that cause hepatic fibrosis in NASH. Nat Rev Gastroenterol Hepatol 10(2):71–72

    Article  Google Scholar 

  41. Noetel A, Kwiecinski M, Elfimova N, Huang J, Odenthal M (2012) MicroRNA are central players in anti- and profibrotic gene regulation during liver fibrosis. Front Physiol 3:49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Roderburg C, Urban GW, Bettermann K, Vucur M, Zimmermann H, Schmidt S et al (2011) Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology 53(1):209–218

    Article  PubMed  CAS  Google Scholar 

  43. Sekiya Y, Ogawa T, Yoshizato K, Ikeda K, Kawada N (2011) Suppression of hepatic stellate cell activation by microRNA-29b. Biochem Biophys Res Commun 412(1):74–79

    Article  PubMed  CAS  Google Scholar 

  44. Roderburg C, Mollnow T, Bongaerts B, Elfimova N, Vargas Cardenas D, Berger K et al (2012) Micro-RNA profiling in human serum reveals compartment-specific roles of miR-571 and miR-652 in liver cirrhosis. PLoS One 7(3):e32999

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Wang B, Li W, Guo K, Xiao Y, Wang Y, Fan J (2012) miR-181b promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients. Biochem Biophys Res Commun 421(1):4–8

    Article  PubMed  CAS  Google Scholar 

  46. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW (2013) Cancer genome landscapes. Science 339(6127):1546–1558

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Lujambio A, Lowe SW (2012) The microcosmos of cancer. Nature 482(7385):347–355

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Zhang R, Wang L, Yu GR, Zhang X, Yao LB, Yang AG (2009) MicroRNA-122 might be a double-edged sword in hepatocellular carcinoma. Hepatology 50(4):1322–1323

    Article  PubMed  Google Scholar 

  49. Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG et al (2007) Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 67(13):6092–6099

    Article  PubMed  CAS  Google Scholar 

  50. Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H et al (2012) Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 122(8):2871–2883

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R et al (2012) MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 122(8):2884–2897

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS (2009) Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene 28(40):3526–3536

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM et al (2009) MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology 49(5):1571–1582

    Article  PubMed  CAS  Google Scholar 

  54. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA et al (2011) An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147(6):1233–1247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q et al (2011) Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 19(2):232–243

    Article  PubMed  CAS  Google Scholar 

  56. Fornari F, Milazzo M, Chieco P, Negrini M, Calin GA, Grazi GL et al (2010) MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res 70(12):5184–5193

    Article  PubMed  CAS  Google Scholar 

  57. Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B (2010) miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A 107(1):264–269

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A (2009) miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16(6):498–509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Meng F, 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. Gastroenterology 133(2):647–658

    Article  PubMed  CAS  Google Scholar 

  60. Huang S, He X (2011) The role of microRNAs in liver cancer progression. Br J Cancer 104(2):235–240

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Marquardt JU, Factor VM, Thorgeirsson SS (2010) Epigenetic regulation of cancer stem cells in liver cancer: current concepts and clinical implications. J Hepatol 53(3):568–577

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A et al (2008) Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47(3):897–907

    Article  PubMed  CAS  Google Scholar 

  63. Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S et al (2009) MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 361(15):1437–1447

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Yang X, Liang L, Zhang XF, Jia HL, Qin Y, Zhu XC et al (2013) MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology 58(1):158–170

    Article  PubMed  CAS  Google Scholar 

  65. Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X et al (2013) Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest 123(2):630–645

    PubMed  PubMed Central  CAS  Google Scholar 

  66. Tao ZH, Wan JL, Zeng LY, Xie L, Sun HC, Qin LX (2013) miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma. J Exp Med 210(4):789–803

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Wong CM, Wong CC, Lee JM, Fan DN, Au SL, Ng IO (2012) Sequential alterations of microRNA expression in hepatocellular carcinoma development and venous metastasis. Hepatology 55(5):1453–1461

    Article  PubMed  CAS  Google Scholar 

  68. Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B et al (2011) MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology 140(5):1618–1628 e1616

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Sato F, Hatano E, Kitamura K, Myomoto A, Fujiwara T, Takizawa S et al (2011) MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan Criteria. PLoS One 6(1):e16435

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Borel F, Konstantinova P, Jansen PL (2012) Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma. J Hepatol 56(6):1371–1383

    Article  PubMed  CAS  Google Scholar 

  71. Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF et al (2010) Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res 70(23):9798–9807

    Article  PubMed  CAS  Google Scholar 

  72. Zhou J, Yu L, Gao X, Hu J, Wang J, Dai Z et al (2011) Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol 29(36):4781–4788

    Article  PubMed  CAS  Google Scholar 

  73. Qi P, Cheng SQ, Wang H, Li N, Chen YF, Gao CF (2011) Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One 6(12):e28486

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M (2011) Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol 45(4):355–360

    Article  PubMed  CAS  Google Scholar 

  75. Xu J, Wu C, Che X, Wang L, Yu D, Zhang T et al (2011) Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog 50(2):136–142

    Article  PubMed  CAS  Google Scholar 

  76. Liu AM, Yao TJ, Wang W, Wong KF, Lee NP, Fan ST et al (2012) Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open 2(2):e000825

    Article  PubMed  PubMed Central  Google Scholar 

  77. Budhu A, Ji J, Wang XW (2010) The clinical potential of microRNAs. J Hematol Oncol 3:37

    Article  PubMed  PubMed Central  Google Scholar 

  78. Szabo G, Sarnow P, Bala S (2012) MicroRNA silencing and the development of novel therapies for liver disease. J Hepatol 57(2):462–466

    Article  PubMed  CAS  Google Scholar 

  79. Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW et al (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137(6):1005–1017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Callegari E, Elamin BK, Giannone F, Milazzo M, Altavilla G, Fornari F et al (2012) Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology 56(3):1025–1033

    Article  PubMed  CAS  Google Scholar 

  81. Park JK, Kogure T, Nuovo GJ, Jiang J, He L, Kim JH (2011) miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res 71(24):7608–7616

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Ji J, Yu L, Yu Z, Forgues M, Uenishi T, Kubo S et al (2013) Development of a miR-26 companion diagnostic test for adjuvant interferon-alpha therapy in hepatocellular carcinoma. Int J Biol Sci 9(3):303–312

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Takata A, Otsuka M, Yoshikawa T, Kishikawa T, Hikiba Y, Obi S et al (2013) MicroRNA-140 acts as a liver tumor suppressor by controlling NF-kappaB activity by directly targeting DNA methyltransferase 1 (Dnmt1) expression. Hepatology 57(1):162–170

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Au SL, Wong CC, Lee JM, Fan DN, Tsang FH, Ng IO et al (2012) Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology 56(2):622–631

    Article  PubMed  CAS  Google Scholar 

  85. Buurman R, Gurlevik E, Schaffer V, Eilers M, Sandbothe M, Kreipe H (2012) Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 143(3):811–820, e811-815

    Article  PubMed  CAS  Google Scholar 

  86. Yuan JH, Yang F, Chen BF, Lu Z, Huo XS, Zhou WP et al (2011) The histone deacetylase 4/SP1/microrna-200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma. Hepatology 54(6):2025–2035

    Article  PubMed  CAS  Google Scholar 

  87. Yang H, Cho ME, Li TW, Peng H, Ko KS, Mato JM et al (2013) MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. J Clin Invest 123(1):285–298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Marquardt JU, Galle PR (2013) Epigenetic regulation of methionine adenosyltransferase 1A: a role for MicroRNA-based treatment in liver cancer? Hepatology 57(5):2081–2084

    Article  PubMed  Google Scholar 

  89. Marquardt JU, Thorgeirsson SS (2010) Stem cells in hepatocarcinogenesis: evidence from genomic data. Semin Liver Dis 30(1):26–34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355(12):1253–1261

    Article  PubMed  CAS  Google Scholar 

  91. Ji J, Wang XW (2011) Identification of cancer stem cell-related microRNAs in hepatocellular carcinoma. Methods Mol Biol 826:163–175

    Article  Google Scholar 

  92. Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C et al (2009) Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 50(2):472–480

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Wu K, Ding J, Chen C, Sun W, Ning BF, Wen W et al (2012) Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology 56(6):2255–2267

    Article  PubMed  CAS  Google Scholar 

  94. Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO et al (2007) Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132(7):2542–2556

    Article  PubMed  CAS  Google Scholar 

  95. Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A (2010) miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell 7(6):694–707

    Article  PubMed  CAS  Google Scholar 

  96. Cairo S, Wang Y, de Reynies A, Duroure K, Dahan J, Redon MJ et al (2010) Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Proc Natl Acad Sci U S A 107(47):20471–20476

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Thomas M, Lieberman J, Lal A (2010) Desperately seeking microRNA targets. Nat Struct Mol Biol 17(10):1169–1174

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter R. Galle .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Marquardt, J.U., Galle, P.R. (2014). MicroRNAs as Novel Targets in Liver Cancer: Facing the Clinical Challenge. In: Sarkar, F. (eds) MicroRNA Targeted Cancer Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-05134-5_9

Download citation

Publish with us

Policies and ethics