Advertisement

MicroRNAs and Hepatocellular Carcinoma

  • Aldo CavalliniEmail author
Chapter
Part of the Current Clinical Oncology book series (CCO)

Abstract

Genomic studies have demonstrated that many portions of the human genome do not encode conventional protein-coding genes, but encode biologically active noncoding RNA species. One class of such small noncoding RNA is microRNA (miRNA), comprised of a group of well-conserved, small RNA molecules (21-23 nucleotides) that can up- or down-regulate gene expression in normal and abnormal cellular activities by base pairing with 3′ untranslated regions (3′ UTRs) of target messenger RNA (mRNA) [1].

Keywords

miRNA Expression Acute Rejection Orthotopic Liver Transplantation miRNA Profile miRNA Expression Pattern 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

AAV

Adenoviral vector

ADAM9

ADAM metallopeptidase domain 9

AFP

a-fetoprotein

ALT

Allograft transplantation

AMO

Anti-miRNA antisense oligomer

CEA

Carcinoembryonic antigen

DGCR8

DiGeorge syndrome chromosomal region 8

Dicer

Ribonuclease III

Drosha

Double-stranded-RNA-binding protein

5-FU

5-fluorouracil

ITBLs

Ischemic-type biliary lesions

LT

Liver transplantation

miRNA

MicroRNA

mRNA

RNA messenger

OLT

Orthotopic liver transplantation

OncomiR

miRNA with oncogene role

OT

Operational tolerance

pre-miRNA

Preliminary miRNA

pri-miRNA

Primary miRNA

RISC

Multiprotein RNA induced-silencing complex

RNAi

RNA-mediated interference

siRNA

Small interfering RNA

snRNA

Small noncoding RNA

TACE

Transcatheter arterial chemoembolization

TS miR

Tumor Suppressor miRNA

UTR

Untranslated region

XPO5

Exportin 5

ZEN

N,N-diethyl-4-(4-nitronaphthalen-1-ylazo)-phenylamine

References

  1. 1.
    Vasudevan S, Tong Y, Steitz JA. Switching from repression to activation: microRNAs can up-regulate translation. Science. 2007;318:1931–4. doi: 10.1126/science.1149460.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Liu B, Li J, Cairns MJ. Identifying miRNAs, targets and functions. Brief Bioinform. 2014;15:1–19.PubMedCrossRefGoogle Scholar
  4. 4.
    Sassen S, Miska EA, Caldas C. MicroRNA: implications for cancer. Virchows Arch. 2008;452:1–10. PMID: 18040713 doi: 10.1007/s00428-007-0532-2.
  5. 5.
    Xiao ZD, Diao LT, Yang JH, Xu H, Huang MB, Deng YJ, Zhou H, Qu LH. Deciphering the transcriptional regulation of microRNA genes in humans with ACT Locater. Nucleic Acids Res. 2013;41:e5. PMID: 22941648 doi: 10.1093/nar/gks821.
  6. 6.
    Holland B, Wong J, Li M, Rasheed S. Identification of human microRNA-like sequences embedded within the protein-encoding genes of the human immunodeficiency virus. PLoS One. 2013;8:e58586. PMID: 23520522 doi: 10.1371/journal.pone.0058586.
  7. 7.
    Wahid F, Shehzad A, Khan T, Kim YY. MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim Biophys Acta. 2010;1803:1231–43. doi: 10.1016/j.bbamcr.2010.06.013.PubMedCrossRefGoogle Scholar
  8. 8.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99:15524–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kumar MS, Lu J, Mercer KL. GolubTR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang B, Pan X, Cobb GP, Anderson TA. microRNAs as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Wang D, Qiu C, Zhang H, Wang J, Cui Q, Yin Y. Human microRNA oncogenes and tumor suppressors show significantly different biological patterns: from functions to targets. PLoS ONE. 2010;5:e13067. doi: 10.1371/journal.pone.0013067.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Takahashi K, Yan I, Wen HJ, Patel T. microRNAs in liver disease: from diagnostics to therapeutics. Clin Biochem. 2013;46:946–52. doi: 10.1016/j.clinbiochem.2013.01.025.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Yan Y, Luo YC, Wan HY, et al. MicroRNA-10a is involved in the metastatic process by regulating Eph tyrosine kinase receptor A4-mediated epithelial-mesenchymal transition and adhesion in hepatoma cells. Hepatology. 2013;57:667–77.PubMedCrossRefGoogle Scholar
  16. 16.
    Li QJ, Zhou L, Yang F, et al. MicroRNA-10b promotes migration and invasion through CADM1 in human hepatocellular carcinoma cells. Tumour Biol. 2012;33:1455–65.PubMedCrossRefGoogle Scholar
  17. 17.
    Huang XH, Wang Q, Chen JS, Fu XH, Chen XL, Chen LZ, et al. Bead-based microarray analysis of microRNA expression in hepatocellular carcinoma: miR-338 is downregulated. Hepatol Res. 2009;39:786–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Yang F, Yin Y, Wang F, 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. 2010;51:1614–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu WH, Yeh SH, Lu CC, et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology. 2009;136:683–93.PubMedCrossRefGoogle Scholar
  20. 20.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Jiang R, Deng L, Zhao L, et al. miR-22 promotes HBVrelated hepatocellular carcinoma development in males. Clin Cancer Res. 2011;17:5593–603.PubMedCrossRefGoogle Scholar
  23. 23.
    Wang B, Hsu SH, Frankel W, Ghoshal K, Jacob ST. Stat3-mediated activation of microRNA-23a suppresses gluconeogenesis in hepatocellular carcinoma by down-regulating glucose-6-phosphatase and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha. Hepatology. 2012;56:186–97.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Li Y, Tan W, Neo TW, Aung MO, Wasser S, Lim SG, Tan TM. Role of the miR-106b-25 microRNA cluster in hepatocellular carcinoma. Cancer Sci. 2009;100:1234–42. doi: 10.1111/j.1349-7006.2009.01164.x.PubMedCrossRefGoogle Scholar
  25. 25.
    Yang X, Liang L, Zhang XF, Jia HL, Qin Y, Zhu XC, Gao XM, Qiao P, Zheng Y, Sheng YY, Wei JW, Zhou HJ, Ren N, Ye QH, Dong QZ, Qin LX. MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-Stat3 pathway. Hepatology. 2013;58:158–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Yao J, Liang L, Huang S, Ding J, Tan N, Zhao Y, Yan M, Ge C, Zhang Z, Chen T, Wan D, Yao M, Li J, Gu J, He X. MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma. Hepatology. 2010;51:846–56.PubMedGoogle Scholar
  27. 27.
    Jiang J, Gusev Y, Aderca I, Mettler TA, Nagorney DM, Brackett DJ, Roberts LR, Schmittgen TD. Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res. 2008;14:419–27.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Su H, Yang JR, Xu T, Huang J, Xu L, Yuan Y, Zhuang SM. MicroRNA-101, downregulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 2009;69:1135–42.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang TH, Yeh CT, Ho JY, Ng KF, Chen TC. OncomiR miR-96 and miR-182 promote cell proliferation and invasion through targeting ephrinA5 in hepatocellular carcinoma. Mol Carcinog. 2015;. doi: 10.1002/mc.22286.Google Scholar
  30. 30.
    Varnholt H, Drebber U, Schulze F, Wedemeyer I, Schirmacher P, Dienes HP, Odenthal M. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology. 2008;47:1223–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Shen G, Jia H, Tai Q, Li Y, Chen D. miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. Carcinogenesis. 2013;34:211–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Zhang JJ, Wang CY, Hua L, Yao KH, Chen JT, Hu JH. miR-107 promotes hepatocellular carcinoma cell proliferation by targeting Axin2. Int J Clin Exp Pathol. 2015;8:5168–74.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Ma S, Tang KH, Chan YP, Lee TK, Kwan PS, Castilho A, Ng I, Man K, Wong N, To KF, Zheng BJ, Lai PB, Lo CM, Chan KW, Guan XY. miR-130b Promotes CD133(+) liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1. Cell Stem Cell. 2010;7:694–707.PubMedCrossRefGoogle Scholar
  34. 34.
    Liu S, Guo W, Shi J, Li N, Yu X, Xue J, Fu X, Chu K, Lu C, Zhao J, Xie D, Wu M, Cheng S, Liu S. MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma. J Hepatol. 2012;56:389–96.PubMedCrossRefGoogle Scholar
  35. 35.
    Liu LL, Lu SX, Li M, Li LZ, Fu J, Hu W, Yang YZ, Luo RZ, Zhang CZ, Yun JP. FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2. Oncotarget. 2014;5:5113–24.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Zhang X, Liu S, Hu T, Liu S, He Y. Up-regulated SS. microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology. 2009;50:490–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Luedde T. MicroRNA-151 and its hosting gene FAK (focal adhesion kinase) regulate tumor cell migration and spreading of hepatocellular carcinoma. Hepatology. 2010;52:1164–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Yan XL, Jia YL, Chen L, Zeng Q, Zhou JN, Fu CJ, Chen HX, Yuan HF, Li ZW, Shi L, Xu YC, Wang JX, Zhang XM, He LJ, Zhai C, Yue W, Pei XT. Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis. Hepatology. 2013;57:2274–86. doi: 10.1002/hep.26257.PubMedCrossRefGoogle Scholar
  39. 39.
    Wang B, Hsu SH, Majumder S, Kutay H, Huang W, Jacob ST, Ghoshal K. TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene. 2010;29:1787–97.PubMedCrossRefGoogle Scholar
  40. 40.
    Goeppert B, Schmezer P, Dutruel C, Oakes C, Renner M, Breinig M, Warth A, Vogel MN, Mittelbronn M, Mehrabi A, Gdynia G, Penzel R, Longerich T, Breuhahn K, Popanda O, Plass C, Schirmacher P, Kern MA. Downregulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology. 2010;52:2023–33.PubMedCrossRefGoogle Scholar
  41. 41.
    Petrelli A, Perra A, Cora D, Sulas P, Menegon S, Manca C, Migliore C, Kowalik MA, Ledda-Columbano GM, Giordano S, Columbano A. MicroRNA/gene profiling unveils early molecular changes and nuclear factor erythroid related factor 2 (NRF2) activation in a rat model recapitulating human hepatocellular carcinoma (HCC). Hepatology. 2014;59:228–41.PubMedCrossRefGoogle Scholar
  42. 42.
    Ying Q, Liang L, Guo W, Zha R, Tian Q, Huang S, Yao J, Ding J, Bao M, Ge C, Yao M, Li J, He X. Hypoxia-inducible microRNA-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma. Hepatology. 2011;54:2064–75.PubMedCrossRefGoogle Scholar
  43. 43.
    Chen PJ, Yeh SH, Liu WH, Lin CC, Huang HC, Chen CL, Chen DS, Chen PJ. Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis. Hepatology. 2012;56:632–43.PubMedCrossRefGoogle Scholar
  44. 44.
    Xia H, Ooi LL, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology. 2013;58:629–41.PubMedCrossRefGoogle Scholar
  45. 45.
    Bae HJ, Jung KH, Eun JW, Shen Q, Kim HS, Park SJ, Shin WC, Yang HD, Park WS, Lee JY, Nam SW. MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. J Hepatol. 2015;63:408–19. doi: 10.1016/j.jhep.2015.03.019.PubMedCrossRefGoogle Scholar
  46. 46.
    Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, Grazi GL, Croce CM, Bolondi L, Negrini M. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 2007;67:6092–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Lan SH, Wu SY, Zuchini R, Lin XZ, Su IJ, Tsai TF, Lin YJ, Wu CT, Liu HS. Autophagy suppresses tumorigenesis of hepatitis B virus-associated hepatocellular carcinoma through degradation of microRNA-224. Hepatology. 2014;59:505–17.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhou P, Jiang W, Wu L, Chang R, Wu K, Wang Z. miR-301a is a candidate oncogene that targets the homeobox gene Gax in human hepatocellular carcinoma. Dig Dis Sci. 2012;57:1171–80.PubMedCrossRefGoogle Scholar
  49. 49.
    Wu N, Liu X, Xu X, Fan X, Liu M, Li X, Zhong Q, Tang H. MicroRNA-373, a new regulator of protein phosphatase 6, functions as an oncogene in hepatocellular carcinoma. FEBS J. 2011;278:2044–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Yamamoto Y, Kosaka N, Tanaka M, Koizumi F, Kanai Y, Mizutani T, Murakami Y, Kuroda M, Miyajima A, Kato T, Ochiya T. MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma. Biomarkers. 2009;14:529–38.PubMedCrossRefGoogle Scholar
  51. 51.
    Lin J, Huang S, Wu S, Ding J, Zhao Y, Liang L, Tian Q, Zha R, Zhan R, He X. MicroRNA-423 promotes cell growth and regulates G(1)/S transition by targeting p21Cip1/Waf1 in hepatocellular carcinoma. Carcinogenesis. 2011;32:1641–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Yang H, Cho ME, Li TW, Peng H, Ko KS, Mato JM, Lu SC. MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. J Clin Invest. 2013;123:285–98.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhang LY, Liu M, Li X, Tang H. miR-490-3p modulates cell growth and epithelial to mesenchymal transition of hepatocellular carcinoma cells by targeting endoplasmic reticulum-golgi intermediate compartment protein 3 (ERGIC3). J Biol Chem. 2013;288:4035–47.PubMedCrossRefGoogle Scholar
  54. 54.
    Lim L, Balakrishnan A, Huskey N, Jones KD, Jodari M, Ng R, Song G, Riordan J, Anderton B, Cheung ST, Willenbring H, Dupuy A, Chen X, Brown D. Chang. MicroRNA-494 within an oncogenic microRNA megacluster regulates G1/S transition in liver tumorigenesis through suppression of mutated in colorectal cancer. Hepatology. 2014;59:202–15.PubMedCrossRefGoogle Scholar
  55. 55.
    Augello C, Vaira V, Caruso L, Destro A, Maggioni M, Park YN, Montorsi M, Santambrogio R, Roncalli M, Bosari S. MicroRNAs profiling of hepatocarcinogenesis identifies C19MC cluster as a novel prognostic biomarker in hepatocellular carcinoma. Liver Int. 2012;32:772–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, Savic R, Ward SC, Thung S, Chiang DY, Alsinet C, Tovar V, Roayaie S, Schwartz M, Bruix J, Waxman S, Friedman SL, Golub T, Mazzaferro V, Llovet JM. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology. 2011;140:1618–28.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Tian Q, Liang L, Ding J, Zha R, Shi H, Wang Q, Huang S, Guo W, Ge C, Chen T, Li J, He X. MicroRNA-550a acts as a pro-metastatic gene and directly targets cytoplasmic polyadenylation element-binding protein 4 in hepatocellular carcinoma. PLoS ONE. 2012;7:e48958.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Fornari F, Milazzo M, Chieco P, Negrini M, Marasco E, Capranico G, Mantovani V, Marinello J, Sabbioni S, Callegari E, Cescon M, Ravaioli M, Croce CM, Bolondi L, Gramantieri L. In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. J Pathol. 2012;227:275–85.PubMedCrossRefGoogle Scholar
  59. 59.
    Jiang X, Xiang G, Wang Y, Zhang L, Yang X, Cao L, Peng H, Xue P, Chen D. MicroRNA-590-5p regulates proliferation and invasion in human hepatocellular carcinoma cells by targeting TGF-beta RII. Mol Cells. 2012;33:545–51.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    El Tayebi HM, Hosny KA, Esmat G, Breuhahn K, Abdelaziz AI. miR-615-5p is restrictedly expressed in cirrhotic and cancerous liver tissues and its overexpression alleviates the tumorigenic effects in hepatocellular carcinoma. FEBS Lett. 2012;586:3309–16.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang L, Yang L, Liu X, Chen W, Chang L, Chen L, Loera S, Chu P, Huang WC, Liu YR, Yen Y. MicroRNA-657 promotes tumorigenesis in hepatocellular carcinoma by targeting transducin-like enhancer protein 1 through nuclear factor kappa B pathways. Hepatology. 2013;57:1919–30.PubMedCrossRefGoogle Scholar
  62. 62.
    Law PT, Qin H, Ching AK, Lai KP, Co NN, He M, Lung RW, Chan AW, Chan TF, Wong N. Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma. J Hepatol. 2013;58:1165–73.PubMedCrossRefGoogle Scholar
  63. 63.
    Tang, et al. MiR-429 increases the metastatic capability of HCC via regulating classic Wnt pathway rather than epithelial–mesenchymal transition. Cancer Lett. 2015;364:33–43.PubMedCrossRefGoogle Scholar
  64. 64.
    Wang Z, Lin S, Li JJ, Xu Z, Yao H, Zhu X, Xie D, Shen Z, Sze J, Li K, Lu G, Chan DT, Poon WS, Kung HF, Lin MC. MYC protein inhibits transcription of the microRNA cluster MC-let-7a-1, let-7d and let-7f-1 via noncanonical E-box. J Biol Chem. 2011;286:39703–14.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Zhu XM, Wu LJ, Xu J, Yang R, Wu FS. Let-7c microRNA expression and clinical significance in hepatocellular carcinoma. J Int Med Res. 2011;39:2323–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Lan FF, Wang H, Chen YC, Chan CY, Ng SS, Li K, Xie D, He ML, Lin MC, Kung HF. Hsa-let-7g inhibits proliferation of hepatocellular carcinoma cells by downregulation of c-Myc and upregulation of p16(INK4A). Int J Cancer. 2011;128:319–31.PubMedCrossRefGoogle Scholar
  67. 67.
    Li D, Yang P, Li H, Cheng P, Zhang L, Wei D, Su X, Peng J, Gao H, Tan Y, Zhao Z, Li Y, Qi Z, Rui Y, Zhang T. MicroRNA-1 inhibits proliferation of hepatocarcinoma cells by targeting endothelin-1. Life Sci. 2012;91:440–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Fang Y, Xue JL, Shen Q, Chen J, Tian L. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology. 2012;55:1852–62.PubMedCrossRefGoogle Scholar
  69. 69.
    Liao CG, Kong LM, Zhou P, Yang XL, Huang JG, Zhang HL, Lu N. miR-10b is overexpressed in hepatocellular carcinoma and promotes cell proliferation, migration and invasion through RhoC, uPAR and MMPs. J Transl Med. 2014;12:234. doi: 10.1186/s12967-014-0234-x.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Wang Y, Jiang L, Ji X, Yang B, Zhang Y, Fu XD. Hepatitis B viral RNA directly mediates down-regulation of the tumor suppressor microRNA miR-15a/miR-16-1 in hepatocytes. J Biol Chem. 2013;288:18484–93.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Zhu XC, Dong QZ, Zhang XF, Deng B, Jia HL, Ye QH, Qin LX, Wu XZ. microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. Int J Mol Med. 2012;30:1321–6.PubMedGoogle Scholar
  72. 72.
    Fang JH, Zhou HC, Zeng C, Yang J, Liu Y, Huang X, Zhang JP, Guan XY, Zhuang SM. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology. 2011;54:1729–40.PubMedCrossRefGoogle Scholar
  73. 73.
    Bae HJ, Noh JH, Kim JK, Eun JW, Jung KH, Kim MG, Chang YG, Shen Q, Kim SJ, Park WS, Lee JY, Nam SW. MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma. Oncogene. 2014;33:2557–67.Google Scholar
  74. 74.
    Dang Y, Luo D, Rong M, Chen G. Underexpression of miR-34a in hepatocellular carcinoma and its contribution towards enhancement of proliferating inhibitory effects of agents targeting c-MET. PLoS ONE. 2013;8:e61054. doi: 10.1371/journal.pone.0061054.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Li D, Liu X, Lin L, Hou J, Li N, Wang C, Wang P, Zhang Q, Zhang P, Zhou W, Wang Z, Ding G, Zhuang SM, Zheng L, Tao W, Cao X. MicroRNA-99a inhibits hepatocellular carcinoma growth and correlates with prognosis of patients with hepatocellular carcinoma. J Biol Chem. 2011;286:36677–85.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Petrelli A, Perra A, Schernhuber K, Cargnelutti M, Salvi A, Migliore C, Ghiso E, Benetti A, Barlati S, Ledda-Columbano GM, Portolani N, De Petro G, Columbano A, Giordano S. Sequential analysis of multistage hepatocarcinogenesis reveals that miR-100 and PLK1 dysregulation is an early event maintained along tumor progression. Oncogene. 2012;31:4517–26.PubMedCrossRefGoogle Scholar
  77. 77.
    Wang L, Zhang X, Jia LT, Hu SJ, Zhao J, Yang JD, Wen WH, Wang Z, Wang T, Zhao J, Wang RA, Meng YL, Nie YZ, Dou KF, Chen SY, Yao LB, Fan DM, Zhang R, Yang AG. c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma. Hepatology. 2014;59:1850–63.PubMedCrossRefGoogle Scholar
  78. 78.
    Xu J, Zhu X, Wu L, Yang R, Yang Z, Wang Q, Wu F. MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/beta-catenin pathway. Liver Int. 2012;32:752–60.PubMedCrossRefGoogle Scholar
  79. 79.
    Lang Q, Ling C. MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. Biochem Biophys Res Commun. 2012;426:247–52.PubMedCrossRefGoogle Scholar
  80. 80.
    Kim JK, Noh JH, Jung KH, Eun JW, Bae HJ, Kim MG, Chang YG, Shen Q, Park WS, Lee JY, Borlak J, Nam SW. Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology. 2013;57:1055–67.PubMedCrossRefGoogle Scholar
  81. 81.
    Fan Q, He M, Deng X, Wu WK, Zhao L, Tang J, Wen G, Sun X, Liu Y. Derepression of c-Fos caused by microRNA-139 down-regulation contributes to the metastasis of human hepatocellular carcinoma. Cell Biochem Funct. 2013;31:319–24.PubMedCrossRefGoogle Scholar
  82. 82.
    Yang H, Fang F, Chang R, Yang L. MicroRNA-140-5p suppresses tumor growth and metastasis by targeting transforming growth factor beta receptor 1 and fibroblast growth factor 9 in hepatocellular carcinoma. Hepatology. 2013;58:205–17.Google Scholar
  83. 83.
    Banaudha K, Kaliszewski M, Korolnek T, Florea L, Yeung ML, Jeang KT, Kumar A. MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes. Hepatology. 2011;53:53–61.PubMedCrossRefGoogle Scholar
  84. 84.
    Du C, Lv Z, Cao L, Ding C, Gyabaah OA, Xie H, Zhou L, Wu J, Zheng S. MiR-126-3p suppresses tumor metastasis and angiogenesis of hepatocellular carcinoma by targeting LRP6 and PIK3R2. J Transl Med. 2014;12:259. doi: 10.1186/s12967-014-0259-1.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Law PT, Ching AK, Chan AW, Wong QW, Wong CK, To KF, Wong N. MiR-145 modulates multiple components of the insulin-like growth factor pathway in hepatocellular carcinoma. Carcinogenesis. 2012;33:1134–41.PubMedCrossRefGoogle Scholar
  86. 86.
    Gailhouste L, Gomez-Santos L, Hagiwara K, Hatada I, Kitagawa N, Kawaharada K, Thirion M, Kosaka N, Takahashi RU, Shibata T, Miyajima A, Ochiya T. miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells. Hepatology. 2013;58:1153–65.PubMedCrossRefGoogle Scholar
  87. 87.
    Huang J, Wang Y, Guo Y, Sun S. Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology. 2010;52:60–70.PubMedCrossRefGoogle Scholar
  88. 88.
    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.PubMedCrossRefGoogle Scholar
  89. 89.
    Fornari F, Milazzo M, Chieco P, Negrini M, Calin GA, Grazi GL, Pollutri D, Croce CM, Bolondi L, Gramantieri L. MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2010;70:5184–93.PubMedCrossRefGoogle Scholar
  90. 90.
    Shen Q, Cicinnati VR, Zhang X, Iacob S, Weber F, Sotiropoulos GC, Radtke A, Lu M, Paul A, Gerken G, Beckebaum S. Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion. Mol Cancer. 2010;9:227.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    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. 2011;54:1177–84.PubMedCrossRefGoogle Scholar
  92. 92.
    Yuan JH, Yang F, Chen BF, Lu Z, Huo XS, Zhou WP, Wang F, Sun SH. The histone deacetylase 4/SP1/microrna-200a regulatory network contributes to aberrant histone acetylation in hepatocellular carcinoma. Hepatology. 2011;54:2025–35.PubMedCrossRefGoogle Scholar
  93. 93.
    Au SL, Wong CC, Lee JM, Fan DN, Tsang FH, Ng IO, Wong CM. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis. Hepatology. 2012;56:622–31.PubMedCrossRefGoogle Scholar
  94. 94.
    Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, Zucman-Rossi J. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008;47:1955–63.PubMedCrossRefGoogle Scholar
  95. 95.
    Liu Y, Ren F, Rong M, Luo Y, Dang Y, Chen G. Association between underexpression of microrna-203 and clinicopathological significance in hepatocellular carcinoma tissues. Cancer Cell Int. 2015;15:62. doi: 10.1186/s12935-015-0214-0.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Yunqiao L, Vanke H, Jun X, Tangmeng G. MicroRNA-206, down-regulated in hepatocellular carcinoma, suppresses cell proliferation and promotes apoptosis. Hepatogastroenterology. 2014;61:1302–7.Google Scholar
  97. 97.
    Shih TC, Tien YJ, Wen CJ, Yeh TS, Yu MC, Huang CH, Lee YS, Yen TC, Hsieh SY. MicroRNA-214 downregulation contributes to tumor angiogenesis by inducing secretion of the hepatoma-derived growth factor in human hepatoma. J Hepatol. 2012;57:584–91.PubMedCrossRefGoogle Scholar
  98. 98.
    Huang N, Lin J, Ruan J, Su N, Qing R, Liu F, He B, Lv C, Zheng D, Luo R. MiR-219-5p inhibits hepatocellular carcinoma cell proliferation by targeting glypican-3. FEBS Lett. 2012;586:884–91.PubMedCrossRefGoogle Scholar
  99. 99.
    Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 2008;135:257–69.PubMedCrossRefGoogle Scholar
  100. 100.
    Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44:694–8.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Han H, Sun D, Li W, Shen H, Zhu Y, Li C, Chen Y, Lu L, Li W, Zhang J, Tian Y, Li Y. A c-Myc-MicroRNA functional feedback loop affects hepatocarcinogenesis. Hepatology. 2013;57:2378–8239.PubMedCrossRefGoogle Scholar
  102. 102.
    Chang Y, Yan W, He X, Zhang L, Li C, Huang H, Nace G, Geller DA, Lin J, Tsung A. miR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology. 2012;143:177–87.PubMedCrossRefGoogle Scholar
  103. 103.
    Zheng Y, Yin L, Chen H, Yang S, Pan C, Lu S, Miao M, Jiao B. miR-376a suppresses proliferation and induces apoptosis in hepatocellular carcinoma. FEBS Lett. 2012;586:2396–403.PubMedCrossRefGoogle Scholar
  104. 104.
    You X, Liu F, Zhang T, Li Y, Ye L, Zhang X. Hepatitis B virus X protein upregulates oncogene Rab18 to result in the dysregulation of lipogenesis and proliferation of hepatoma cells. Carcinogenesis. 2013;34:1644–52.PubMedCrossRefGoogle Scholar
  105. 105.
    Zhang H, Feng Z, Huang R, Xia Z, Xiang G, Zhang J. MicroRNA-449 suppresses proliferation of hepatoma cell lines through blockade lipid metabolic pathway related to SIRT1. Int J Oncol. 2014;45:2143–52. doi: 10.3892/ijo.2014.2596.PubMedGoogle Scholar
  106. 106.
    Weng Z, Wang D, Zhao W, Song M, You F, Yang L, Chen L. microRNA-450a targets DNA methyltransferase 3a in hepatocellular carcinoma. Exp Ther Med. 2011;2:951–5.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Zhang S, Shan C, Kong G, Du Y, Ye L, Zhang X. MicroRNA-520e suppresses growth of hepatoma cells by targeting the NF-kappaB-inducing kinase (NIK). Oncogene. 2012;31:3607–20.PubMedCrossRefGoogle Scholar
  108. 108.
    Tao ZH, Wan JL, Zeng LY, Xie L, Sun HC, Qin LX, Wang L, Zhou J, Ren ZG, Li YX, Fan J, Wu WZ. miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma. J Exp Med. 2013;210:789–803.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Zhang JF, He ML, Fu WM, Wang H, Chen LZ, Zhu X, Chen Y, Xie D, Lai P, Chen G, Lu G, Lin MC, Kung HF. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. Hepatology. 2011;54:2137–48.PubMedCrossRefGoogle Scholar
  110. 110.
    Maurel M, Jalvy S, Ladeiro Y, Combe C, Vachet L, Sagliocco F, Bioulac-Sage P, Pitard V, Jacquemin-Sablon H, Zucman-Rossi J, Laloo B, Grosset CF. A functional screening identifies five microRNAs controlling glypican-3: role of miR-1271 down-regulation in hepatocellular carcinoma. Hepatology. 2013;57:195–204.PubMedCrossRefGoogle Scholar
  111. 111.
    Li G, Yang F, Xu H, Yue Z, Fang X, Liu J. MicroRNA-708 is downregulated in hepatocellular carcinoma and suppresses tumor invasion and migration. Biomed Pharmacother. 2015;73:154–9. doi: 10.1016/j.biopha.2015.05.010.PubMedCrossRefGoogle Scholar
  112. 112.
    Yu P, Wu D, You Y, Sun J, Lu L, Tan J, Bie P. miR-208-3p promotes hepatocellular carcinoma cell proliferation and invasion through regulating ARID2 expression. Exp Cell Res. 2015;336:232–41. doi: 10.1016/j.yexcr.2015.07.008.PubMedCrossRefGoogle Scholar
  113. 113.
    Zhai J, Qu S, Li X, Zhong J, Chen X, Qu Z, Wu D. miR-129 suppresses tumor cell growth and invasion by targeting PAK5 in hepatocellular carcinoma. Biochem Biophys Res Commun. 2015;464:161–7. doi: 10.1016/j.bbrc.2015.06.108.PubMedCrossRefGoogle Scholar
  114. 114.
    Pan L, Ren F, Rong M, Dang Y, Luo Y, Luo D, Chen G. Correlation between down-expression of miR-431 and clinicopathological significance in HCC tissues. Clin Transl Oncol. 2015;17:557–63. doi: 10.1007/s12094-015-1278-y.PubMedCrossRefGoogle Scholar
  115. 115.
    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M. Circulating microRNAs as stable bloodbased markers for cancer detection. Proc Natl Acad Sci USA. 2008;105:10513–8.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 2011;39:7223–33.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Koberle V, Kronenberger B, Pleli T, Trojan J, Imelmann E, Peveling-Oberhag J, Welker MW, Elhendawy M, Zeuzem S, Piiper A, Waidmann O. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer. 2013;49:3442–9. doi: 10.1016/j.ejca.2013.06.002.
  119. 119.
    Castoldi M, Spasic MV, Altamura S, et al. The liver-specific micro-RNA miR-122 controls systemic iron homeostasis in mice. J Clin Invest. 2011;121:1386–96.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Qi P, Cheng SQ, Wang H, Li N, Chen YF, Gao CF. Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection. PLoS One. 2011;6:e28486. doi: 10.1371/journal.pone.0028486.
  121. 121.
    Nasheri N, Singaravelu R, Goodmurphy M, et al. Competing roles of miR-122 recognition elements in hepatitis C virus RNA. Virology. 2011;410:336–44.PubMedCrossRefGoogle Scholar
  122. 122.
    Meng FL, Wang W, Jia WD. Diagnostic and prognostic significance of serum miR-24-3p in HBV-related hepatocellular carcinoma. Med Oncol. 2014;31:177. doi: 10.1007/s12032-014-0177-3.
  123. 123.
    Tomimaru Y, Eguchi H, Nagano H, Wada H, Kobayashi S, Marubashi S, Tanemura M, Tomokuni A, Takemasa I, Umeshita K, Kanto T, Doki Y, Mori M. Circulating microRNA-21 as a novel biomarker for hepatocellular carcinoma. J Hepatol. 2012;56:167–175. doi: 10.1016/j.jhep.2011.04.026.
  124. 124.
    Zhan MX, Li Y, Hu BS, Shao PJ, Meng QW, He X, Huang JW, Lu LG. Expression of serum microRNAs (miR-222, miR-181, miR-216) in human hepatocellular carcinoma and its clinical significance. Zhonghua Yi Xue Za Zhi. 2013;93:1830–2.PubMedGoogle Scholar
  125. 125.
    Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, Huang L, Li H, Tan W, Wang C, Lin D. Circulating microRNAs, miR-21, miR-122, and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog. 2011;50:136–42. doi: 10.1002/mc.20712.
  126. 126.
    Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M. Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol. 2011;45:355–60.PubMedCrossRefGoogle Scholar
  127. 127.
    Tan Y, Ge G, Pan T, Wen D, Chen L, Yu X, Zhou X, Gan J. A serum microRNA panel as potential biomarkers for hepatocellular carcinoma related with hepatitis B virus. PLoS One. 2014;9:e107986. doi: 10.1371/journal.pone.0107986.
  128. 128.
    Wen Y, Han J, Chen J, Dong J, Xia Y, Liu J, Jiang Y, Dai J, Lu J, Jin G, Han J, Wei Q, Shen H, Sun B, Hu Z. Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int J Cancer. 2015;137:1679–90. doi: 10.1002/ijc.29544.
  129. 129.
    Li LM, Hu ZB, Zhou ZX, Chen X, Liu FY, Zhang JF, Shen HB, Zhang CY, Zen K. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 2010;70:9798–9807. doi: 10.1158/0008-5472.CAN-10-1001.
  130. 130.
    Lin XJ, Chong Y, Guo ZW, Xie C, Yang XJ, Zhang Q, Li SP, Xiong Y, Yuan Y, Min J, Jia WH, Jie Y, Chen MS, Chen MX, Fang JH, Zeng C, Zhang Y, Guo RP, Wu Y, Lin G, Zheng L, Zhuang SM. A serum microRNA classifier for early detection of hepatocellular carcinoma: a multicentre, retrospective, longitudinal biomarker identification study with a nested case-control study. Lancet Oncol. 2015;16:804–15. doi: 10.1016/S1470-2045(15)00048-0.PubMedCrossRefGoogle Scholar
  131. 131.
    Forner A. Hepatocellular carcinoma surveillance with miRNAs. Lancet Oncol. 2015;16:743–5. doi: 10.1016/S1470-2045(15)00014-5.PubMedCrossRefGoogle Scholar
  132. 132.
    Li G, Shen Q, Li C, Li D, Chen J, He M. Identification of circulating MicroRNAs as novel potential biomarkers for hepatocellular carcinoma detection: a systematic review and meta-analysis. Clin Transl Oncol. 2015;17:684–93. doi: 10.1007/s12094-015-1294-y.PubMedCrossRefGoogle Scholar
  133. 133.
    Barry CT, D’Souza M, McCall M, Safadjou S, Ryan C, Kashyap R, Marroquin C, Orloff M, Almudevar A, Godfrey TE. Micro RNA expression profiles as adjunctive data to assess the risk of hepatocellular carcinoma recurrence after liver transplantation. Am J Transplant. 2012;12:428–37. doi: 10.1111/j.1600-6143.2011.03788.x.PubMedCrossRefGoogle Scholar
  134. 134.
    Han ZB, Zhong L, Teng MJ, Fan JW, Tang HM, Wu JY, Chen HY, Wang ZW, Qiu GQ, Peng ZH. Identification of recurrence-related microRNAs in hepatocellular carcinoma following liver transplantation. Mol Oncol. 2012;6:445–57. doi: 10.1016/j.molonc.2012.04.001.PubMedCrossRefGoogle Scholar
  135. 135.
    Morita M, Chen J, Fujino M, Kitazawa Y, Sugioka A, Zhong L, Li XK. Identification of microRNAs involved in acute rejection and spontaneous tolerance in murine hepatic allografts. Sci Rep. 2014;4:6649. doi: 10.1038/srep06649.PubMedCrossRefGoogle Scholar
  136. 136.
    Farid WR, Verhoeven CJ, de Jonge J, Metselaar HJ, Kazemier G, van der Laan LJ. The ins and outs of microRNAs as biomarkers in liver disease and transplantation. Transpl Int. 2014;12:1222–32. doi: 10.1111/tri.12379.CrossRefGoogle Scholar
  137. 137.
    Farid WR, Pan Q, van der Meer AJ, de Ruiter PE, Ramakrishnaiah V, de Jonge J, Kwekkeboom J, Janssen HL, Metselaar HJ, Tilanus HW, Kazemier G, van der Laan LJ. Hepatocyte-derived miRs as serum biomarker of hepatic injury and rejection after liver transplantation. Liver Transpl. 2012;18:290–7.PubMedCrossRefGoogle Scholar
  138. 138.
    Verhoeven CJ, Farid WR, de Ruiter PE, Hansen BE, Roest HP, de Jonge J, Kwekkeboom J, Metselaar HJ, Tilanus HW, Kazemier G, van der Laan LJ. MicroRNA profiles in graft preservation solution are predictive of ischemic-type biliary lesions after liver transplantation. J Hepatol. 2013;59:1231–8. doi: 10.1016/j.jhep.2013.07.034.PubMedCrossRefGoogle Scholar
  139. 139.
    Lankisch TO, Voigtlander T, Manns MP, Holzmann A, Dangwal S, Thum T. MicroRNAs in the bile of patients with biliary strictures after liver transplantation. Liver Transpl. 2014;20:673–8. doi: 10.1002/lt.23872.PubMedCrossRefGoogle Scholar
  140. 140.
    Alex Bishop G, Bertolino PD, Bowen DG, McCaughan GW. Tolerance in liver transplantation. Best Pract Res Clin Gastroenterol. 2012;26:73–84. doi: 10.1016/j.bpg.2012.01.003.
  141. 141.
    Qian S, Fung JJ, Demetris AJ. Starzl TE (1991) Allogeneic orthotopic liver transplantation in mice: a preliminary study of rejection across well-defined MHC barriers. Transplant Proc. 1991;23:705–6.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Wang Y, Tian Y, Ding Y, Wang J, Yan S, Zhou L, Xie H, Chen H, Li H, Zhang J, Zhao J, Zheng S. MiR-152 may silence translation of CaMK II and induce spontaneous immune tolerance in mouse liver transplantation. PLoS ONE. 2014;9:e105096. doi: 10.1371/journal.pone.0105096.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Yang Z, Miao R, Li G, Wu Y, Robson SC, Yang X, Zhao Y, Zhao H, Zhong Y. Identification of recurrence related microRNAs in hepatocellular carcinoma after surgical resection. Int J Mol Sci. 2013;14:1105–18. doi: 10.3390/ijms14011105.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Chan EY, Larson AM, Fix OK, Yeh MM, Levy AE, Bakthavatsalam R, Halldorson JB, Reyes JD, Perkins JD. Identifying risk for recurrent hepatocellular carcinoma after liver transplantation: implications for surveillance studies and new adjuvant therapies. Liver Transpl. 2008;14:956–65. doi: 10.1002/lt.21449.PubMedCrossRefGoogle Scholar
  145. 145.
    Hagiwara K, Ochiya T, Kosaka N. A paradigm shift for extracellular vesicles as small RNA carriers: from cellular waste elimination to therapeutic applications. Drug Deliv Transl Res. 2014;4:31–7.PubMedCrossRefGoogle Scholar
  146. 146.
    Sugimachi K, Matsumura T, Hirata H, Uchi R, Ueda M, Ueo H, Shinden Y, Iguchi T, Eguchi H, Shirabe K, Ochiya T, Maehara Y, Mimori K. Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation. Br J Cancer. 2015;112:532–8. doi: 10.1038/bjc.2014.621.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Hu J, Wang Z, Tan CJ, Liao BY, Zhang X, Xu M, Dai Z, Qiu SJ, Huang XW, Sun J, Sun QM, He YF, Song K, Pan Q, Wu Y, Fan J, Zhou J. Plasma microRNA, a potential biomarker for acute rejection after liver transplantation. Transplantation. 2013;95:991–9. doi: 10.1097/TP.0b013e31828618d8.PubMedCrossRefGoogle Scholar
  148. 148.
    Wei L, Gong X, Martinez OM, Krams SM. Differential expression and functions of microRNAs in liver transplantation and potential use as non-invasive biomarkers. Transpl Immunol. 2013;29:123–9. doi: 10.1016/j.trim.2013.08.005.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Gehrau RC, Mas VR, Villami FG, Dumur CI, Mehta NK, Suh JL, Maluf DG. MiR signature at the time of clinical HCV recurrence associates with aggressive fibrosis post-liver transplantation. Am J Transpl. 2013;13:729–37.CrossRefGoogle Scholar
  150. 150.
    Joshi D, Salehi S, Brereton H, Arno M, Quaglia A, Heaton N, O’Grady J, Agarwal K, Aluvihare V. Distinct microRNA profiles are associated with the severity of hepatitis C virus recurrence and acute cellular rejection after liver transplantation. Liver Transpl. 2013;19:383–94. doi: 10.1002/lt.23613.PubMedCrossRefGoogle Scholar
  151. 151.
    Gelley F, Zadori G, Nemes B, Fassan M, Lendvai G, Sarvary E, Doros A, Gerlei Z, Nagy P, Schaff Z, Kiss A. MicroRNA profile before and after antiviral therapy in liver transplant recipients for hepatitis C virus cirrhosis. J Gastroenterol Hepatol. 2014;29:121–7. doi: 10.1111/jgh.12362.PubMedCrossRefGoogle Scholar
  152. 152.
    Amrouche L, Rabant M, Anglicheau D. MicroRNAs as biomarkers of graft outcome. Transplant Rev (Orlando). 2014;28:111–8. doi: 10.1016/j.trre.2014.03.003.CrossRefGoogle Scholar
  153. 153.
    Liu WL, Gao M, Tzen KY, Tsai CL, Hsu FM, Cheng AL, Cheng JC. Targeting phosphatidylinositide3-Kinase/Akt pathway by BKM120 for radiosensitization in hepatocellular carcinoma. Oncotarget. 2014;5(11):3662–72.PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Zhang Y, Zheng L, Ding Y, Li Q, Wang R, Liu T, Sun Q, Yang H, Peng S, Wang W, Chen L. MiR-20a induces cell radioresistance by activating the PTEN/PI3 K/Akt signaling pathway in hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2015;92(5):1132–40. doi: 10.1016/j.ijrobp.2015.04.007.PubMedCrossRefGoogle Scholar
  155. 155.
    Zhan M, Li Y, Hu B, He X, Huang J, Zhao Y, Fu S, Lu L. Serum microRNA-210 as a predictive biomarker for treatment response and prognosis in patients with hepatocellular carcinoma undergoing transarterial chemoembolization. J Vasc Interv Radiol. 2014;25:1279–87.PubMedCrossRefGoogle Scholar
  156. 156.
    El-Halawany MS, Ismail HM, Zeeneldin AA, Elfiky A, Tantawy M, Kobaisi MH, Hamed I, Abdel Wahab AH. Investigating the pretreatment miRNA expression patterns of advanced hepatocellular carcinoma patients in association with response to TACE treatment. Biomed Res Int. 2015;2015:649750. doi: 10.1155/2015/649750.
  157. 157.
    Tomimaru Y, Eguchi H, Nagano H, Wada H, Tomokuni A, Kobayashi S, Marubashi S, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M. MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer. 2010;103:1617–26. doi: 10.1038/sj.bjc.6605958.
  158. 158.
    Tomokuni A, Eguchi H, Tomimaru Y, Wada H, Kawamoto K, Kobayashi S, Marubashi S, Tanemura M, Nagano H, Mori M, Doki Y. miR-146a suppresses the sensitivity to interferon-α in hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2011;414:675–80. doi: 10.1016/j.bbrc.2011.09.124.
  159. 159.
    Ma J, Guo R, Wang T, Pan X, Lei X. Let-7b binding site polymorphism in the B-cell lymphoma-extra large 3’UTR is associated with fluorouracil resistance of hepatocellular carcinoma. Mol Med Rep 2015; 11: 677–81. doi: 10.3892/mmr.2014.2692.
  160. 160.
    Qin J, Luo M, Qian H, Chen W. Upregulated miR-182 increases drug resistance in cisplatin-treated HCC cell by regulating TP53INP1. Gene. 2014;538:342–47. doi: 10.1016/j.gene.2013.12.043.
  161. 161.
    Ma J, Wang T, Guo R, Yang X, Yin J, Yu J, Xiang Q, Pan X, Zu X, Peng C, Tang H, Lei X. MicroRNA-133a and microRNA-326 co-contribute to hepatocellular carcinoma 5-fluorouracil and cisplatin sensitivity by directly targeting B-cell lymphoma-extra large. Mol Med Rep. 2015;12:6235–40. doi: 10.3892/mmr.2015.4134.PubMedGoogle Scholar
  162. 162.
    Fornari F, Gramantieri L, Giovannini C, Veronese A, Ferracin M, Sabbioni S, Calin GA, Grazi GL, Croce CM, Tavolari S, Chieco P, Negrini M, Bolondi L. MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2009;69:5761–7.PubMedCrossRefGoogle Scholar
  163. 163.
    Fornari F, Milazzo M, Chieco P, Negrini M, Calin GA, Grazi GL, Pollutri D, Croce CM, Bolondi L, Gramantieri L. MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res. 2010;70(12):5184–93. doi: 10.1158/0008-5472.CAN-10-0145.PubMedCrossRefGoogle Scholar
  164. 164.
    Zhang J, Wang Y, Zhen P, Luo X, Zhang C, Zhou L, Lu Y, Yang Y, Zhang W, Wan J. Genome-wide analysis of miRNA signature differentially expressed in doxorubicin-resistant and parental human hepatocellular carcinoma cell lines. PLoS ONE. 2013;8(1):e54111. doi: 10.1371/journal.pone.0054111.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Zhou C, Liu J, Li Y, Liu L, Zhang X, Ma CY, et al. microRNA-1274a, a modulator of sorafenib induced a disintegrin and metalloproteinase 9 (ADAM9) down-regulation in hepatocellular carcinoma. FEBS Lett. 2011;585:1828–34.PubMedCrossRefGoogle Scholar
  166. 166.
    Bai S, Nasser MW, Wang B, Hsu SH, Datta J, Kutay H, Yadav A, Nuovo G, Kumar P, Ghoshal K. MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem. 2009;284:32015–3227. doi: 10.1074/jbc.M109.016774.
  167. 167.
    Yang F, Li QJ, Gong ZB, Zhou L, You N, Wang S, Li XL, Li JJ, An JZ, Wang DS, He Y, Dou KF. MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment. Technol Cancer Res Treat. 2014;13:77–86. doi: 10.7785/tcrt.2012.500364.
  168. 168.
    Liu K, Liu S, Zhang W, Ji B, Wang Y, Liu Y. miR-222 regulates sorafenib resistance and enhance tumorigenicity in hepatocellular carcinoma. Int J Oncol. 2014;45:1537–46. doi: 10.3892/ijo.2014.2577.
  169. 169.
    Stiuso P, Potenza N, Lombardi A, Ferrandino I, Monaco A, Zappavigna S, Vanacore D, Mosca N, Castiello F, Porto S, Addeo R, Prete SD, De Vita F, Russo A, Caraglia M. MicroRNA-423-5p promotes autophagy in cancer cells and is increased in serum from hepatocarcinoma patients treated with sorafenib. Mol Ther Nucleic Acids. 2015;4:e233. doi: 10.1038/mtna.2015.8.PubMedCrossRefGoogle Scholar
  170. 170.
    Vaira V, Roncalli M, Carnaghi C, Faversani A, Maggioni M, Augello C, Rimassa L, Pressiani T, Spagnuolo G, Di Tommaso L, Fagiuoli S, Rota Caremoli E, Barberis M, Labianca R, Santoro A, Bosari S. MicroRNA-425-3p predicts response to sorafenib therapy in patients with hepatocellular carcinoma. Liver Int. 2015;35(3):1077–86. doi: 10.1111/liv.12636.
  171. 171.
    Peveling-Oberhag J, Döring C, Hartmann S, Filmann N, Mertens A, Piiper A, Herrmann E, Hansmann ML, Zeuzem S, Trojan J, Welker MW. Feasibility of global miRNA analysis from fine-needle biopsy FFPE material in patients with hepatocellular carcinoma treated with sorafenib. Clin Sci (Lond). 2015;128:29–37. doi: 10.1042/CS20140007.CrossRefGoogle Scholar
  172. 172.
    Huang S, He R, Rong M, Dang Y, Chen G. Synergistic effect of MiR-146a mimic and cetuximab on hepatocellular carcinoma cells. Biomed Res Int. 2014;2014:384121. doi: 10.1155/2014/384121.PubMedPubMedCentralGoogle Scholar
  173. 173.
    Rong M, He R, Dang Y, Chen G. Expression and clinicopathological significance of miR-146a in hepatocellular carcinoma tissues. Ups J Med Sci. 2014;119:19–24. doi: 10.3109/03009734.2013.856970.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Zhao J, Kelnar K, Bader AG. In-depth analysis shows synergy between erlotinib and miR-34a. PLoS ONE. 2014;9(2):e89105. doi: 10.1371/journal.pone.0089105.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Mirna Therapeutics. Press Release: Mirna Therapeutics is First to Advance MicroRNA into the Clinic for Cancer. Corporate website. 2013.Google Scholar
  176. 176.
    Bader AG, Brown D, Winkler M. The promise of microRNA replacement therapy. Cancer Res. 2010;70(18):7027–30. doi: 10.1158/0008-5472.CAN-10-2010.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Zhang Y, Wang Z, Gemeinhart RA. Progress in microRNA delivery. J Control Release. 2013;172:962–74. doi: 10.1016/j.jconrel.2013.09.015.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature. 2005;438:685–9.PubMedCrossRefGoogle Scholar
  179. 179.
    Lennox KA, Owczarzy R, Thomas DM, Walder JA, Behlke MA. Improved performance of anti-miRNA oligonucleotides using a novel non-nucleotide modifier. Mol Ther Nucleic Acids. 2013;27(2):e117. doi: 10.1038/mtna.2013.46.CrossRefGoogle Scholar
  180. 180.
    Tsai WC, Hsu PW, Lai TC, et al. MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology. 2009;49:1571–82.PubMedCrossRefGoogle Scholar
  181. 181.
    Zhu Y, Lu Y, Zhang Q, et al. MicroRNA-26a/b and their host genes cooperate to inhibit the G1/S transition by activating the pRb protein. Nucleic Acids Res. 2012;40:4615–25.PubMedCrossRefGoogle Scholar
  182. 182.
    Callegari E, Elamin BK, Giannone F, et al. Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology. 2012;56:1025–33.PubMedCrossRefGoogle Scholar
  183. 183.
    Kota J, Chivukula RR, O’Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005–17.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Park JK, Kogure T, Nuovo GJ, Jiang J, He L, Kim JH, Phelps MA, Papenfuss TL, Croce CM, Patel T. Schmittgen TD.miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res. 2011;71:7608–16.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Ma L, Liu J, Shen J, Liu L, Wu J, Li W, Luo J, Chen Q, Qian C. Expression of miR-122 mediated by adenoviral vector induces apoptosis and cell cycle arrest of cancer cells. Cancer Biol Ther. 2010;9:554–61.PubMedCrossRefGoogle Scholar
  186. 186.
    Wagenaar TR, Zabludoff S, Ahn SM, Allerson C, Arlt H, Baffa R, Cao H, Davis S, Garcia-Echeverria C, Gaur R, Huang SM, Jiang L, Kim D, Metz-Weidmann C, Pavlicek A, Pollard J, Reeves J, Rocnik JL, Scheidler S, Shi C, Sun F, Tolstykh T, Weber W, Winter C, Yu E, Yu Q, Zheng G, Wiederschain D. Anti-miR-21 suppresses hepatocellular carcinoma growth via broad transcriptional network deregulation. Mol Cancer Res. 2015;13:1009–10021. doi: 10.1158/1541-7786.MCR-14-0703.PubMedCrossRefGoogle Scholar
  187. 187.
    van Rooij E, Purcell AL, Levin AA. Developing microRNA therapeutics. Circ Res. 2012;110:496–507.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Laboratory of Cellular and Molecular Biology, Dept. Clinical PathologyIRCCS, Saverio de BellisCastellana GrotteItaly

Personalised recommendations