Science China Life Sciences

, Volume 55, Issue 10, pp 906–919 | Cite as

The role and clinical implications of microRNAs in hepatocellular carcinoma

  • Xue Zhao
  • Zhen Yang
  • GuangBing Li
  • DongKai Li
  • Yi Zhao
  • Yan Wu
  • Simon C. Robson
  • Lian He
  • YiYao XuEmail author
  • RuoYu MiaoEmail author
  • HaiTao ZhaoEmail author
Open Access


Hepatocellular carcinoma (HCC) is common and one of the most aggressive of all human cancers. Recent studies have indicated that miRNAs, a class of small noncoding RNAs that regulate gene expression post-transcriptionally, directly contribute to HCC by targeting many critical regulatory genes. Several miRNAs are involved in hepatitis B or hepatitis C virus replication and virus-induced changes, whereas others participate in multiple intracellular signaling pathways that modulate apoptosis, cell cycle checkpoints, and growth-factor-stimulated responses. When disturbed, these pathways appear to result in malignant transformation and ultimately HCC development. Recently, miRNAs circulating in the blood have acted as possible early diagnostic markers for HCC. These miRNA also could serve as indicators with respect to drug efficacy and be prognostic in HCC patients. Such biomarkers would assist stratification of HCC patients and help direct personalized therapy. Here, we summarize recent advances regarding the role of miRNAs in HCC development and progression. Our expectation is that these and ongoing studies will contribute to the understanding of the multiple roles of these small noncoding RNAs in liver tumorigenesis.


miRNA noncoding RNAs hepatocellular carcinoma cancer therapy 


  1. 1.
    Berry D A, Herbst R S, Rubin E H. Reports from the 2010 Clinical and Translational Cancer Research Think Tank meeting: design strategies for personalized therapy trials. Clin Cancer Res, 2012, 18: 638–644PubMedPubMedCentralGoogle Scholar
  2. 2.
    Liu L, Miao R, Yang H, et al. Prognostic factors after liver resection for hepatocellular carcinoma: a single-center experience from China. Am J Surg, 2012, 203: 741–750PubMedGoogle Scholar
  3. 3.
    El-Serag H B, Marrero J A, Rudolph L, et al. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology, 2008,134: 1752–1763PubMedGoogle Scholar
  4. 4.
    Huynh H. Tyrosine kinase inhibitors to treat liver cancer. Expert Opin Emerg Drugs, 2010, 15: 13–26PubMedGoogle Scholar
  5. 5.
    Razumilava N, Gores G J. Sorafenib for HCC: a pragmatic perspective. Oncology (Williston Park), 2011, 25: 300, 302Google Scholar
  6. 6.
    Blum H E. Hepatocellular carcinoma: therapy and prevention. World J Gastroenterol, 2005, 11: 7391–7400PubMedGoogle Scholar
  7. 7.
    Cho Y K. A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria. Ann Surg, 2011, 254: 838–839PubMedGoogle Scholar
  8. 8.
    Chen J W, Kow L, Verran D J, et al. Poorer survival in patients whose explanted hepatocellular carcinoma (HCC) exceeds Milan or UCSF Criteria. An analysis of liver transplantation in HCC in Australia and New Zealand. HPB (Oxford), 2009, 11: 81–89Google Scholar
  9. 9.
    Calin G A, Croce C M. MicroRNA signatures in human cancers. Nat Rev Cancer, 2006, 6: 857–866PubMedGoogle Scholar
  10. 10.
    Lu X, Zhao H, Yang H, et al. A prospective clinical study on early recurrence of hepatocellular carcinoma after hepatectomy. J Surg Oncol, 2009, 100: 488–493PubMedGoogle Scholar
  11. 11.
    Clinkenbeard E L, Butler J E, Spear B T. Pericentral activity of AFP enhancer E3 and glutamine synthetase upstream enhancer in the adult liver are regulated by beta-catenin. Hepatology, 2012Google Scholar
  12. 12.
    Petri A, Lindow M, Kauppinen S. MicroRNA silencing in primates: towards development of novel therapeutics. Cancer Res, 2009, 69: 393–395PubMedGoogle Scholar
  13. 13.
    Mott J L. MicroRNAs involved in tumor suppressor and oncogene pathways: implications for hepatobiliary neoplasia. Hepatology, 2009, 50: 630–637PubMedPubMedCentralGoogle Scholar
  14. 14.
    Feng Y, Yu X. Cardinal roles of miRNA in cardiac development and disease. Sci China Life Sci, 2011, 54: 1113–1120PubMedGoogle Scholar
  15. 15.
    Zhang Y, Dong D, Yang B. Atrial remodeling in atrial fibrillation and association between microRNA network and atrial fibrillation. Sci China Life Sci, 2011, 54: 1097–1102PubMedGoogle Scholar
  16. 16.
    Feng W, Feng Y. MicroRNAs in neural cell development and brain diseases. Sci China Life Sci, 2011, 54: 1103–1112PubMedGoogle Scholar
  17. 17.
    Luo J, Teng M, Fan J, et al. Marek’s disease virus-encoded microRNAs: genomics, expression and function. Sci China Life Sci, 2010, 53: 1174–1180PubMedGoogle Scholar
  18. 18.
    Zuo J, Wang Y, Liu H, et al. MicroRNAs in tomato plants. Sci China Life Sci, 2011, 54: 599–605PubMedGoogle Scholar
  19. 19.
    He S, Yang Z, Skogerbo G, et al. The properties and functions of virus encoded microRNA, siRNA, and other small noncoding RNAs. Crit Rev Microbiol, 2008, 34: 175–188PubMedGoogle Scholar
  20. 20.
    Visone R, Petrocca F, Croce C M. Micro-RNAs in gastrointestinal and liver disease. Gastroenterology, 2008, 135: 1866–1869PubMedGoogle Scholar
  21. 21.
    Montalto G, Cervello M, Giannitrapani L, et al. Epidemiology, risk factors, and natural history of hepatocellular carcinoma. Ann N Y Acad Sci, 2002, 963: 13–20PubMedGoogle Scholar
  22. 22.
    Yang C, Wei W. The miRNA expression profile of the uveal melanoma. Sci China Life Sci, 2011, 54: 351–358PubMedGoogle Scholar
  23. 23.
    Wu J, Wang C, Du Z, et al. Identification of Pns12 as the second silencing suppressor of Rice gall dwarf virus. Sci China Life Sci, 2011, 54: 201–208PubMedGoogle Scholar
  24. 24.
    Wang X, Zhao H, Xu Q, et al. HPtaa database-potential target genes for clinical diagnosis and immunotherapy of human carcinoma. Nucleic Acids Res, 2006, 34: D607–612PubMedPubMedCentralGoogle Scholar
  25. 25.
    Zhang X, Zhang H, Ye L. Effects of hepatitis B virus X protein on the development of liver cancer. J Lab Clin Med, 2006, 147: 58–66PubMedGoogle Scholar
  26. 26.
    Wang Y, Cui F, Lv Y, et al. HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice. Hepatology, 2004, 39: 318–324PubMedGoogle Scholar
  27. 27.
    Lara-Pezzi E, Majano P L, Yanez-Mo M, et al. Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. J Hepatol, 2001, 34: 409–415PubMedGoogle Scholar
  28. 28.
    Xia L M, Huang W J, Wu J G, et al. HBx protein induces expression of MIG and increases migration of leukocytes through activation of NF-kappaB. Virology, 2009, 385: 335–342PubMedGoogle Scholar
  29. 29.
    Chung T W, Lee Y C, Kim C H. Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J, 2004, 18: 1123–1125PubMedGoogle Scholar
  30. 30.
    Zhang F, Wang Q, Ye L, et al. Hepatitis B virus X protein upregulates expression of calpain small subunit 1 via nuclear factor-kappaB/p65 in hepatoma cells. J Med Virol, 2010, 82: 920–928PubMedGoogle Scholar
  31. 31.
    Zhang X, Liu S, Hu T, et al. Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology, 2009, 50: 490–499PubMedGoogle Scholar
  32. 32.
    Yin Y, Zhao Y, Wang J, et al. antiCODE: a natural sense-antisense transcripts database. BMC Bioinformatics, 2007, 8: 319PubMedPubMedCentralGoogle Scholar
  33. 33.
    Gao W, Yu Y, Cao H, et al. Deregulated expression of miR-21, miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis. Biomed Pharmacother, 2010, 64: 399–408PubMedGoogle Scholar
  34. 34.
    Kitade Y, Akao Y. MicroRNAs and their therapeutic potential for human diseases: microRNAs, miR-143 and -145, function as anti-oncomirs and the application of chemically modified miR-143 as an anti-cancer drug. J Pharmacol Sci, 2010, 114: 276–280PubMedGoogle Scholar
  35. 35.
    Dasari V R, Kaur K, Velpula K K, et al. Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway. PLoS ONE, 2010, 5: e10350PubMedPubMedCentralGoogle Scholar
  36. 36.
    Du B, Ma L M, Huang M B, et al. High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells. FEBS Lett, 2010, 584: 811–816PubMedGoogle Scholar
  37. 37.
    Narbus C M, Israelow B, Sourisseau M, et al. HepG2 cells expressing microRNA miR-122 support the entire hepatitis C virus life cycle. J Virol, 2011, 85: 12087–12092PubMedPubMedCentralGoogle Scholar
  38. 38.
    Cui Y, Su W Y, Xing J, et al. MiR-29a inhibits cell proliferation and induces cell cycle arrest through the downregulation of p42.3 in human gastric cancer. PLoS ONE, 2011, 6: e25872PubMedPubMedCentralGoogle Scholar
  39. 39.
    Dudek H, Datta S R, Franke T F, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science, 1997, 275: 661–665PubMedGoogle Scholar
  40. 40.
    Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology, 2007, 133: 647–658PubMedPubMedCentralGoogle Scholar
  41. 41.
    Garofalo M, Di Leva G, Romano G, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell, 2009, 16: 498–509PubMedPubMedCentralGoogle Scholar
  42. 42.
    Kong G, Zhang J, Zhang S, et al. Upregulated microRNA-29a by hepatitis B virus X protein enhances hepatoma cell migration by targeting PTEN in cell culture model. PLoS ONE, 2011, 6: e19518PubMedPubMedCentralGoogle Scholar
  43. 43.
    Korenaga M, Wang T, Li Y, et al. Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem, 2005, 280: 37481–37488PubMedGoogle Scholar
  44. 44.
    Irshad M, Dhar I. Hepatitis C virus core protein: an update on its molecular biology, cellular functions and clinical implications. Med Princ Pract, 2006, 15: 405–416PubMedGoogle Scholar
  45. 45.
    Pedersen I M, Cheng G, Wieland S, et al. Interferon modulation of cellular microRNAs as an antiviral mechanism. Nature, 2007, 449: 919–922PubMedPubMedCentralGoogle Scholar
  46. 46.
    Hou W, Tian Q, Zheng J, et al. MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins. Hepatology, 2010, 51: 1494–1504PubMedPubMedCentralGoogle Scholar
  47. 47.
    Shan Y, Lambrecht R W, Ghaziani T, et al. Role of Bach-1 in regulation of heme oxygenase-1 in human liver cells: insights from studies with small interfering RNAS. J Biol Chem, 2004, 279: 51769–51774PubMedGoogle Scholar
  48. 48.
    Hornstein E, Mansfield J H, Yekta S, et al. The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature, 2005, 438: 671–674PubMedGoogle Scholar
  49. 49.
    Kitamuro T, Takahashi K, Ogawa K, et al. Bach1 functions as a hypoxia-inducible repressor for the heme oxygenase-1 gene in human cells. J Biol Chem, 2003, 278: 9125–9133PubMedGoogle Scholar
  50. 50.
    Shan Y, Zheng J, Lambrecht R W, et al. Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes in human hepatocytes. Gastroenterology, 2007, 133: 1166–1174PubMedPubMedCentralGoogle Scholar
  51. 51.
    Zhu Z, Wilson A T, Mathahs M M, et al. Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury. Hepatology, 2008, 48: 1430–1439PubMedPubMedCentralGoogle Scholar
  52. 52.
    Elbirt K K, Bonkovsky H L. Heme oxygenase: recent advances in understanding its regulation and role. Proc Assoc Am Physicians, 1999, 111: 438–447PubMedGoogle Scholar
  53. 53.
    Lohmann V, Korner F, Koch J, et al. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science, 1999, 285: 110–113PubMedGoogle Scholar
  54. 54.
    Chang J, Nicolas E, Marks D, et al. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol, 2004, 1: 106–113PubMedGoogle Scholar
  55. 55.
    Lanford R E, Hildebrandt-Eriksen E S, Petri A, et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science, 2010, 327: 198–201PubMedPubMedCentralGoogle Scholar
  56. 56.
    Wang G, Dong X, Hu J, et al. Long-term ex vivo monitoring of in vivo microRNA activity in liver using a secreted luciferase sensor. Sci China Life Sci, 2011, 54: 418–425PubMedGoogle Scholar
  57. 57.
    Jopling C L, Norman K L, Sarnow P. Positive and negative modulation of viral and cellular mRNAs by liver-specific microRNA miR-122. Cold Spring Harb Symp Quant Biol, 2006, 71: 369–376PubMedGoogle Scholar
  58. 58.
    Young D D, Connelly C M, Grohmann C, et al. Small molecule modifiers of microRNA miR-122 function for the treatment of hepatitis C virus infection and hepatocellular carcinoma. J Am Chem Soc, 2010, 132: 7976–7981PubMedGoogle Scholar
  59. 59.
    Moradpour D, Penin F, Rice C M. Replication of hepatitis C virus. Nat Rev Microbiol, 2007, 5: 453–463PubMedGoogle Scholar
  60. 60.
    Song Y, Friebe P, Tzima E, et al. The hepatitis C virus RNA 3′-untranslated region strongly enhances translation directed by the internal ribosome entry site. J Virol, 2006, 80: 11579–11588PubMedPubMedCentralGoogle Scholar
  61. 61.
    Bradrick S S, Walters R W, Gromeier M. The hepatitis C virus 3′-untranslated region or a poly(A) tract promote efficient translation subsequent to the initiation phase. Nucleic Acids Res, 2006, 34: 1293–1303PubMedPubMedCentralGoogle Scholar
  62. 62.
    Isken O, Baroth M, Grassmann C W, et al. Nuclear factors are involved in hepatitis C virus RNA replication. RNA, 2007, 13: 1675–1692PubMedPubMedCentralGoogle Scholar
  63. 63.
    Niepmann M. Activation of hepatitis C virus translation by a liver-specific microRNA. Cell Cycle, 2009, 8: 1473–1477PubMedGoogle Scholar
  64. 64.
    Norman K L, Sarnow P. Modulation of hepatitis C virus RNA abundance and the isoprenoid biosynthesis pathway by microRNA miR-122 involves distinct mechanisms. J Virol, 2010, 84: 666–670PubMedPubMedCentralGoogle Scholar
  65. 65.
    Jopling C L, Yi M, Lancaster A M, et al. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science, 2005, 309: 1577–1581PubMedGoogle Scholar
  66. 66.
    Appel N, Bartenschlager R. A novel function for a micro RNA: negative regulators can do positive for the hepatitis C virus. Hepatology, 2006, 43: 612–615PubMedGoogle Scholar
  67. 67.
    Banaudha K, Kaliszewski M, Korolnek T, et al. MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes. Hepatology, 2011, 53: 53–61PubMedGoogle Scholar
  68. 68.
    Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J Pathol, 2008, 216: 418–427PubMedGoogle Scholar
  69. 69.
    Liu X, Wang T, Wakita T, et al. Systematic identification of microRNA and messenger RNA profiles in hepatitis C virus-infected human hepatoma cells. Virology, 2010, 398: 57–67PubMedGoogle Scholar
  70. 70.
    Yang Z, Ren F, Liu C, et al. dbDEMC: a database of differentially expressed miRNAs in human cancers. BMC Genomics, 2010, 11: S5PubMedPubMedCentralGoogle Scholar
  71. 71.
    Li H P, Leu Y W, Chang Y S. Epigenetic changes in virus-associated human cancers. Cell Res, 2005, 15: 262–271PubMedGoogle Scholar
  72. 72.
    Huang J, Wang Y, Guo Y, et al. Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology, 2010, 52: 60–70PubMedGoogle Scholar
  73. 73.
    Datta J, Kutay H, Nasser M W, et al. Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res, 2008, 68: 5049–5058PubMedPubMedCentralGoogle Scholar
  74. 74.
    Law P T, Wong N. Emerging roles of microRNA in the intracellular signaling networks of hepatocellular carcinoma. J Gastroenterol Hepatol, 2011, 26: 437–449PubMedGoogle Scholar
  75. 75.
    Shimizu S, Takehara T, Hikita H, et al. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol, 2010, 52: 698–704PubMedGoogle Scholar
  76. 76.
    Tsang W P, Kwok T T. Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis in human cancer cells. J Nutr Biochem, 2010, 21: 140–146PubMedGoogle Scholar
  77. 77.
    Tsuruta T, Kozaki K, Uesugi A, et al. miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. Cancer Res, 2011, 71: 6450–6462PubMedGoogle Scholar
  78. 78.
    Tsang T Y, Tang W Y, Chan J Y, et al. P-glycoprotein enhances radiation-induced apoptotic cell death through the regulation of miR-16 and Bcl-2 expressions in hepatocellular carcinoma cells. Apoptosis, 2011, 16: 524–535PubMedGoogle Scholar
  79. 79.
    Sang X, Zhao H, Lu X, et al. Prediction and identification of tumor-specific noncoding RNAs from human UniGene. Med Oncol, 2010, 27: 894–898PubMedGoogle Scholar
  80. 80.
    Chen W S, Leung C M, Pan H W, et al. Silencing of miR-1-1 and miR-133a-2 cluster expression by DNA hypermethylation in colorectal cancer. Oncol Rep, 2012, 28: 1069–1076PubMedGoogle Scholar
  81. 81.
    Chung G E, Yoon J H, Myung S J, et al. High expression of microRNA-15b predicts a low risk of tumor recurrence following curative resection of hepatocellular carcinoma. Oncol Rep, 2010, 23: 113–119PubMedGoogle Scholar
  82. 82.
    Zhang Y. Progress, challenges and new concepts in microRNAs. Sci China Life Sci, 2011, 54: 1096PubMedGoogle Scholar
  83. 83.
    Pineau P, Volinia S, McJunkin K, et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA, 2010, 107: 264–269PubMedPubMedCentralGoogle Scholar
  84. 84.
    Xu C, Liu S, Fu H, et al. MicroRNA-193b regulates proliferation, migration and invasion in human hepatocellular carcinoma cells. Eur J Cancer, 2010, 46: 2828–2836PubMedGoogle Scholar
  85. 85.
    Furuta M, Kozaki K I, Tanaka S, et al. miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis, 2010, 31: 766–776PubMedGoogle Scholar
  86. 86.
    Zhao W Y, Wang D D, Song M Q, et al. Role of microRNA-223 and its target gene oncogene c-myc in hepatocellular carcinoma pathogenesis (in Chinese). Zhonghua Gan Zang Bing Za Zhi, 2011, 19: 114–117PubMedGoogle Scholar
  87. 87.
    Cheng J, Zhou L, Xie Q F, et al. The impact of miR-34a on protein output in hepatocellular carcinoma HepG2 cells. Proteomics, 2010, 10: 1557–1572PubMedGoogle Scholar
  88. 88.
    Hu L, Ibrahim S, Liu C, et al. Thrombin induces tumor cell cycle activation and spontaneous growth by down-regulation of p27Kip1, in association with the up-regulation of Skp2 and MiR-222. Cancer Res, 2009, 69: 3374–3381PubMedPubMedCentralGoogle Scholar
  89. 89.
    Fornari F, Milazzo M, Chieco P, et al. MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res, 2010, 70: 5184–5193PubMedGoogle Scholar
  90. 90.
    Henry J C, Park J K, Jiang J, et al. miR-199a-3p targets CD44 and reduces proliferation of CD44 positive hepatocellular carcinoma cell lines. Biochem Biophys Res Commun, 2010, 403: 120–125PubMedPubMedCentralGoogle Scholar
  91. 91.
    Orian-Rousseau V, Chen L, Sleeman J P, et al. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev, 2002, 16: 3074–3086PubMedPubMedCentralGoogle Scholar
  92. 92.
    Mitchell P S, Parkin R K, Kroh E M, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA, 2008, 105: 10513–10518PubMedPubMedCentralGoogle Scholar
  93. 93.
    Chen X, Ba Y, Ma L, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res, 2008, 18: 997–1006PubMedGoogle Scholar
  94. 94.
    Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS ONE, 2008, 3: e3148PubMedPubMedCentralGoogle Scholar
  95. 95.
    Wang Q Z, Xu W, Habib N, et al. Potential uses of microRNA in lung cancer diagnosis, prognosis, and therapy. Curr Cancer Drug Targets, 2009, 9: 572–594PubMedGoogle Scholar
  96. 96.
    Sukata T, Sumida K, Kushida M, et al. Circulating microRNAs, possible indicators of progress of rat hepatocarcinogenesis from early stages. Toxicol Lett, 2011, 200: 46–52PubMedGoogle Scholar
  97. 97.
    Zhou J, Yu L, Gao X, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma. J Clin Oncol, 2011, 29: 4781–4788PubMedGoogle Scholar
  98. 98.
    Gui J, Tian Y, Wen X, et al. Serum microRNA characterization identifies miR-885-5p as a potential marker for detecting liver pathologies. Clin Sci (Lond), 2011, 120: 183–193Google Scholar
  99. 99.
    Li L M, Hu Z B, Zhou Z X, et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res, 2010, 70: 9798–9807PubMedGoogle Scholar
  100. 100.
    Qu K Z, Zhang K, Li H, et al. Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol, 2011, 45: 355–360PubMedGoogle Scholar
  101. 101.
    Li J, Wang Y, Yu W, et al. Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. Biochem Biophys Res Commun, 2011, 406: 70–73PubMedGoogle Scholar
  102. 102.
    Miao R Y, Zhao H T, Yang H Y, et al. Postoperative adjuvant antiviral therapy for hepatitis B/C virus-related hepatocellular carcinoma: a meta-analysis. World J Gastroenterol, 2010, 16: 2931–2942PubMedPubMedCentralGoogle Scholar
  103. 103.
    Xu J, Wu C, Che X, et al. Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog, 2011, 50: 136–142PubMedGoogle Scholar
  104. 104.
    Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer, 2003, 39: 1990–2005PubMedGoogle Scholar
  105. 105.
    Landgraf P, Rusu M, Sheridan R, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell, 2007, 129: 1401–1414PubMedPubMedCentralGoogle Scholar
  106. 106.
    Barshack I, Meiri E, Rosenwald S, et al. Differential diagnosis of hepatocellular carcinoma from metastatic tumors in the liver using microRNA expression. Int J Biochem Cell Biol, 2010, 42: 1355–1362PubMedGoogle Scholar
  107. 107.
    Wong C C, Wong C M, Tung E K, et al. The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2. Gastroenterology, 2011, 140: 322–331PubMedGoogle Scholar
  108. 108.
    Sato F, Hatano E, Kitamura K, et al. MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan Criteria. PLoS ONE, 2011, 6: e16435PubMedPubMedCentralGoogle Scholar
  109. 109.
    Wong Q W, Ching A K, Chan A W, et al. MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling. Clin Cancer Res, 2010, 16: 867–875PubMedGoogle Scholar
  110. 110.
    Ji J, Zhao L, Budhu A, et al. Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma. J Hepatol, 2010, 52: 690–697PubMedPubMedCentralGoogle Scholar
  111. 111.
    Budhu A, Jia H L, Forgues M, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology, 2008, 47: 897–907PubMedGoogle Scholar
  112. 112.
    Cheng A L, Kang Y K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2009, 10: 25–34PubMedGoogle Scholar
  113. 113.
    Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res, 2006, 66: 11851–11858PubMedGoogle Scholar
  114. 114.
    Cominetti M R, Martin A C, Ribeiro J U, et al. Inhibition of platelets and tumor cell adhesion by the disintegrin domain of human ADAM9 to collagen I under dynamic flow conditions. Biochimie, 2009, 91: 1045–1052PubMedGoogle Scholar
  115. 115.
    Josson S, Anderson C S, Sung S Y, et al. Inhibition of ADAM9 expression induces epithelial phenotypic alterations and sensitizes human prostate cancer cells to radiation and chemotherapy. Prostate, 2011, 71: 232–240PubMedPubMedCentralGoogle Scholar
  116. 116.
    Peduto L. ADAM9 as a potential target molecule in cancer. Curr Pharm Des, 2009, 15: 2282–2287PubMedGoogle Scholar
  117. 117.
    Xu Q, Liu X, Cai Y, et al. RNAi-mediated ADAM9 gene silencing inhibits metastasis of adenoid cystic carcinoma cells. Tumour Biol, 2010, 31: 217–224PubMedGoogle Scholar
  118. 118.
    Zhou C, Liu J, Li Y, e al. microRNA-1274a, a modulator of sorafenib induced a disintegrin and metalloproteinase 9 (ADAM9) down-regulation in hepatocellular carcinoma. FEBS Lett, 2011, 585: 1828–1834PubMedGoogle Scholar
  119. 119.
    Bai S, Nasser M W, Wang B, et al. MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem, 2009, 284: 32015–32027PubMedPubMedCentralGoogle Scholar
  120. 120.
    Ji J, Shi J, Budhu A, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med, 2009, 361: 1437–1447PubMedPubMedCentralGoogle Scholar
  121. 121.
    Calin G A, Dumitru C D, Shimizu M, et al. Frequent deletions and down-regulation of microRNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA, 2002, 99: 15524–15529PubMedPubMedCentralGoogle Scholar
  122. 122.
    He L, Thomson J M, Hemann M T, et al. A microRNA polycistron as a potential human oncogene. Nature, 2005, 435: 828–833PubMedPubMedCentralGoogle Scholar
  123. 123.
    O’Donnell K A, Wentzel E A, Zeller K I, et al. c-Myc-regulated microRNAs modulate E2F1 expression. Nature, 2005, 435: 839–843PubMedGoogle Scholar
  124. 124.
    Kutay H, Bai S, Datta J, et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem, 2006, 99: 671–678PubMedPubMedCentralGoogle Scholar
  125. 125.
    Jiang Q, Wang Y, Hao Y, et al. miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Res, 2009, 37: D98–104PubMedPubMedCentralGoogle Scholar
  126. 126.
    Sarver A L, Phalak R, Thayanithy V, et al. S-MED: sarcoma microRNA expression database. Lab Invest, 2010, 90: 753–761PubMedGoogle Scholar
  127. 127.
    Calin G A, Sevignani C, Dumitru C D, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA, 2004, 101: 2999–3004PubMedPubMedCentralGoogle Scholar
  128. 128.
    Chen H, Chen Q, Fang M, et al. microRNA-181b targets MLK2 in HL-60 cells. Sci China Life Sci, 2010, 53: 101–106PubMedGoogle Scholar
  129. 129.
    Lu J, Getz G, Miska E A, et al. MicroRNA expression profiles classify human cancers. Nature, 2005, 435: 834–838PubMedGoogle Scholar
  130. 130.
    Kanehisa M, Araki M, Goto S, et al. KEGG for linking genomes to life and the environment. Nucleic Acids Res, 2008, 36: D480–484PubMedPubMedCentralGoogle Scholar
  131. 131.
    Xiangji L, Feng X, Qingbao C, et al. Knockdown of HBV surface antigen gene expression by a lentiviral microRNA-based system inhibits HBV replication and HCC growth. J Viral Hepat, 2011, 18: 653–660PubMedGoogle Scholar
  132. 132.
    Jin W B, Wu F L, Kong D, et al. HBV-encoded microRNA candidate and its target. Comput Biol Chem, 2007, 31: 124–126PubMedGoogle Scholar
  133. 133.
    Ely A, Naidoo T, Mufamadi S, et al. Expressed anti-HBV primary microRNA shuttles inhibit viral replication efficiently in vitro and in vivo. Mol Ther, 2008, 16: 1105–1112PubMedGoogle Scholar
  134. 134.
    Chen G, Wang C, Shi T. Overview of available methods for diverse RNA-Seq data analyses. Sci China Life Sci, 2011, 54: 1121–1128PubMedGoogle Scholar
  135. 135.
    Qiu L, Fan H, Jin W, et al. miR-122-induced down-regulation of HO-1 negatively affects miR-122-mediated suppression of HBV. Biochem Biophys Res Commun, 2010, 398: 771–777PubMedGoogle Scholar
  136. 136.
    Li S, Yu B, Wang Y, et al. Identification and functional annotation of novel microRNAs in the proximal sciatic nerve after sciatic nerve transection. Sci China Life Sci, 2011, 54: 806–812PubMedGoogle Scholar
  137. 137.
    Hao M, Zheng S, Ding H, et al. Regulation of microRNA-122 on HBV replication by targeting HBx sequence (in Chinese). Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 2011, 28: 784–789, 803PubMedGoogle Scholar
  138. 138.
    Su C, Hou Z, Zhang C, et al. Ectopic expression of microRNA-155 enhances innate antiviral immunity against HBV infection in human hepatoma cells. Virol J, 2011, 8: 354PubMedPubMedCentralGoogle Scholar
  139. 139.
    de Veer M J, Sledz C A, Williams B R. Detection of foreign RNA: implications for RNAi. Immunol Cell Biol, 2005, 83: 224–228PubMedGoogle Scholar
  140. 140.
    Grimm D, Streetz K L, Jopling C L, et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature, 2006, 441: 537–541PubMedGoogle Scholar
  141. 141.
    Kim D H, Rossi J J. Strategies for silencing human disease using RNA interference. Nat Rev Genet, 2007, 8: 173–184PubMedGoogle Scholar
  142. 142.
    Shah Y M, Morimura K, Yang Q, et al. Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation. Mol Cell Biol, 2007, 27: 4238–4247PubMedPubMedCentralGoogle Scholar
  143. 143.
    Lan F F, Wang H, Chen Y C, et al. Hsa-let-7g inhibits proliferation of hepatocellular carcinoma cells by downregulation of c-Myc and upregulation of p16(INK4A). Int J Cancer, 2011, 128: 319–331PubMedGoogle Scholar
  144. 144.
    Skawran B, Steinemann D, Becker T, et al. Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma. Mod Pathol, 2008, 21: 1479–1489PubMedGoogle Scholar
  145. 145.
    Wu G, Yu F, Xiao Z, et al. Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro. Br J Cancer, 2011, 105: 146–153PubMedPubMedCentralGoogle Scholar
  146. 146.
    Connolly E, Melegari M, Landgraf P, 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: 856–864PubMedPubMedCentralGoogle Scholar

Copyright information

© The Author (s) 2012

Authors and Affiliations

  1. 1.Department of Liver Surgery, Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
  2. 2.School of Life ScienceFudan UniversityShanghaiChina
  3. 3.Department of Liver Transplantation and Hepatobiliary SurgeryProvincial Hospital Affiliated to Shandong UniversityJinanChina
  4. 4.Bioinformatics Research Group, Center for Advanced Computing Technology ResearchInstitute of Computing Technology, Chinese Academy of SciencesBeijingChina
  5. 5.Liver Center and Transplant Institute, Department of Medicine, Beth Israel Deaconess Medical CenterHarvard UniversityBostonUSA

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