Download PDF
Semin Liver Dis 2015; 35(01): 063-074
DOI: 10.1055/s-0034-1397350
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Noncoding RNA as Therapeutic Targets for Hepatocellular Carcinoma

Joseph George
1   Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida
,
Tushar Patel
2   Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, Florida
› Author Affiliations
Further Information

Publication History

Publication Date:
29 January 2015 (online)

   Permissions and Reprints

Abstract

Recent studies have suggested that noncoding RNAs (ncRNAs) contribute to the pathogenesis and progression of hepatocellular carcinoma (HCC). These RNA genes may be involved in various pathobiological processes such as cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Aberrant expression of ncRNA resulting from deregulated epigenetic, transcriptional, or posttranscriptional activity has been described in several studies. ncRNAs are comprised of a highly diverse group of transcripts that include microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) as well as several other types of RNA genes. Understanding the molecular mechanisms by which ncRNA contribute to hepatocarcinogenesis may enable the design of ncRNA-based therapeutics for HCC. In this review, the authors provide a perspective on therapeutic applications based on the emerging evidence of a contributory role of miRNAs and lncRNAs to the pathogenesis and progression of HCC. In addition, ncRNAs that are deregulated in expression in HCC may have utility as potential prognostic or diagnostic markers.

Keywords

hepatocellular carcinoma - noncoding RNA - microRNA - long noncoding RNA - biomarker
 

  • References

  • 1 Chun JM, Kwon HJ, Sohn J , et al. Prognostic factors after early recurrence in patients who underwent curative resection for hepatocellular carcinoma. J Surg Oncol 2011; 103 (2) 148-151
    CrossrefPubMedGoogle Scholar
  • 2 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61 (2) 69-90
    CrossrefPubMedGoogle Scholar
  • 3 Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011; 12 (12) 861-874
    CrossrefPubMedGoogle Scholar
  • 4 Mattick JS, Makunin IV. Non-coding RNA. Hum Mol Genet 2006; 15 (Spec No 1): R17-R29
    CrossrefPubMedGoogle Scholar
  • 5 Braconi C, Valeri N, Kogure T , et al. Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc Natl Acad Sci U S A 2011; 108 (2) 786-791
    CrossrefPubMedGoogle Scholar
  • 6 Morris KV , Ed. Non-Coding RNAs and Epigenetic Regulation of Gene Expression: Drivers of Natural Selection. Norfolk, England: Caister Academic Press; 2012
    Google Scholar
  • 7 Qu Z, Adelson DL. Evolutionary conservation and functional roles of ncRNA. Front Genet 2012; 3: 205
    PubMedGoogle Scholar
  • 8 Shukla GC, Singh J, Barik S. MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol 2011; 3 (3) 83-92
    PubMedGoogle Scholar
  • 9 Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136 (2) 215-233
    CrossrefPubMedGoogle Scholar
  • 10 Sassen S, Miska EA, Caldas C. MicroRNA: implications for cancer. Virchows Arch 2008; 452 (1) 1-10
    PubMedGoogle Scholar
  • 11 Li C, Feng Y, Coukos G, Zhang L. Therapeutic microRNA strategies in human cancer. AAPS J 2009; 11 (4) 747-757
    CrossrefPubMedGoogle Scholar
  • 12 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 (3) e58586
    CrossrefPubMedGoogle Scholar
  • 13 Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature 2008; 455 (7209) 58-63
    CrossrefPubMedGoogle Scholar
  • 14 Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol 2014; 9: 287-314
    CrossrefPubMedGoogle Scholar
  • 15 Braconi C, Henry JC, Kogure T, Schmittgen T, Patel T. The role of microRNAs in human liver cancers. Semin Oncol 2011; 38 (6) 752-763
    CrossrefPubMedGoogle Scholar
  • 16 Lujambio A, Lowe SW. The microcosmos of cancer. Nature 2012; 482 (7385) 347-355
    CrossrefPubMedGoogle Scholar
  • 17 Chu R, Mo G, Duan Z , et al. miRNAs affect the development of hepatocellular carcinoma via dysregulation of their biogenesis and expression. Cell Commun Signal 2014; 12: 45
    CrossrefPubMedGoogle Scholar
  • 18 Datta J, Kutay H, Nasser MW , et al. Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis. Cancer Res 2008; 68 (13) 5049-5058
    CrossrefPubMedGoogle Scholar
  • 19 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 (6) 1852-1862
    CrossrefPubMedGoogle Scholar
  • 20 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 (25) 18484-18493
    CrossrefPubMedGoogle Scholar
  • 21 Bonci D, Coppola V, Musumeci M , et al. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities. Nat Med 2008; 14 (11) 1271-1277
    CrossrefPubMedGoogle Scholar
  • 22 Chen L, Jiang M, Yuan W, Tang H. miR-17-5p as a novel prognostic marker for hepatocellular carcinoma. J Invest Surg 2012; 25 (3) 156-161
    CrossrefPubMedGoogle Scholar
  • 23 Murakami Y, Yasuda T, Saigo K , et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene 2006; 25 (17) 2537-2545
    CrossrefPubMedGoogle Scholar
  • 24 Li Y, Tan W, Neo TW , et al. Role of the miR-106b-25 microRNA cluster in hepatocellular carcinoma. Cancer Sci 2009; 100 (7) 1234-1242
    CrossrefPubMedGoogle Scholar
  • 25 Tan W, Li Y, Lim SG, Tan TM. miR-106b-25/miR-17-92 clusters: polycistrons with oncogenic roles in hepatocellular carcinoma. World J Gastroenterol 2014; 20 (20) 5962-5972
    CrossrefPubMedGoogle Scholar
  • 26 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 (2) 647-658
    CrossrefPubMedGoogle Scholar
  • 27 Zhou L, Yang ZX, Song WJ , et al. MicroRNA-21 regulates the migration and invasion of a stem-like population in hepatocellular carcinoma. Int J Oncol 2013; 43 (2) 661-669
    PubMedGoogle Scholar
  • 28 Su ZX, Zhao J, Rong ZH, Geng WM, Wu YG, Qin CK. Upregulation of microRNA-25 associates with prognosis in hepatocellular carcinoma. Diagn Pathol 2014; 9: 47
    CrossrefPubMedGoogle Scholar
  • 29 Kota J, Chivukula RR, O'Donnell KA , et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 2009; 137 (6) 1005-1017
    CrossrefPubMedGoogle Scholar
  • 30 Yang X, Zhang XF, Lu X , et al. MicroRNA-26a suppresses angiogenesis in human hepatocellular carcinoma by targeting hepatocyte growth factor-cMet pathway. Hepatology 2014; 59 (5) 1874-1885
    CrossrefPubMedGoogle Scholar
  • 31 Xiong Y, Fang JH, Yun JP , et al. Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 2010; 51 (3) 836-845
    PubMedGoogle Scholar
  • 32 Parpart S, Roessler S, Dong F , et al. Modulation of miR-29 expression by α-fetoprotein is linked to the hepatocellular carcinoma epigenome. Hepatology 2014; 60 (3) 872-883
    PubMedGoogle Scholar
  • 33 Xie K, Liu J, Chen J , et al. Methylation-associated silencing of microRNA-34b in hepatocellular carcinoma cancer. Gene 2014; 543 (1) 101-107
    CrossrefPubMedGoogle Scholar
  • 34 Li N, Fu H, Tie Y , et al. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett 2009; 275 (1) 44-53
    CrossrefPubMedGoogle Scholar
  • 35 Aguda BD, Kim Y, Piper-Hunter MG, Friedman A, Marsh CB. MicroRNA regulation of a cancer network: consequences of the feedback loops involving miR-17-92, E2F, and Myc. Proc Natl Acad Sci U S A 2008; 105 (50) 19678-19683
    CrossrefPubMedGoogle Scholar
  • 36 Xu D, He XX, Chang Y, Sun SZ, Xu CR, Lin JS. Downregulation of MiR-93 expression reduces cell proliferation and clonogenicity of HepG2 cells. Hepatogastroenterology 2012; 59 (120) 2367-2373
    PubMedGoogle Scholar
  • 37 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 (1) 211-219
    CrossrefPubMedGoogle Scholar
  • 38 Gramantieri L, Ferracin M, Fornari F , et al. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res 2007; 67 (13) 6092-6099
    CrossrefPubMedGoogle Scholar
  • 39 Tsai WC, Hsu SD, Hsu CS , et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 2012; 122 (8) 2884-2897
    CrossrefPubMedGoogle Scholar
  • 40 Zheng F, Liao YJ, Cai MY , et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut 2012; 61 (2) 278-289
    CrossrefPubMedGoogle Scholar
  • 41 Lu Y, Yue X, Cui Y, Zhang J, Wang K. MicroRNA-124 suppresses growth of human hepatocellular carcinoma by targeting STAT3. Biochem Biophys Res Commun 2013; 441 (4) 873-879
    CrossrefPubMedGoogle Scholar
  • 42 Kim JK, Noh JH, Jung KH , et al. Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology 2013; 57 (3) 1055-1067
    CrossrefPubMedGoogle Scholar
  • 43 Gong J, Zhang JP, Li B , et al. MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene 2013; 32 (25) 3071-3079
    CrossrefPubMedGoogle Scholar
  • 44 Chen H, Miao R, Fan J , et al. Decreased expression of miR-126 correlates with metastatic recurrence of hepatocellular carcinoma. Clin Exp Metastasis 2013; 30 (5) 651-658
    CrossrefPubMedGoogle Scholar
  • 45 Wei X, Tan C, Tang C , et al. Epigenetic repression of miR-132 expression by the hepatitis B virus x protein in hepatitis B virus-related hepatocellular carcinoma. Cell Signal 2013; 25 (5) 1037-1043
    CrossrefPubMedGoogle Scholar
  • 46 Zhao J, Wang W, Huang Y , et al. HBx elevates oncoprotein AEG-1 expression to promote cell migration by downregulating miR-375 and miR-136 in malignant hepatocytes. DNA Cell Biol 2014; 33 (10) 715-722
    CrossrefPubMedGoogle Scholar
  • 47 Liu Y, Ding Y, Huang J , et al. MiR-141 suppresses the migration and invasion of HCC cells by targeting Tiam1. PLoS ONE 2014; 9 (2) e88393
    CrossrefPubMedGoogle Scholar
  • 48 Wang Y, Hu C, Cheng J , et al. MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling. Biochem Biophys Res Commun 2014; 446 (4) 1255-1260
    CrossrefPubMedGoogle Scholar
  • 49 Yang XW, Zhang LJ, Huang XH , et al. miR-145 suppresses cell invasion in hepatocellular carcinoma cells: miR-145 targets ADAM17. Hepatol Res 2014; 44 (5) 551-559
    CrossrefPubMedGoogle Scholar
  • 50 Zhu K, Pan Q, Zhang X , et al. MiR-146a enhances angiogenic activity of endothelial cells in hepatocellular carcinoma by promoting PDGFRA expression. Carcinogenesis 2013; 34 (9) 2071-2079
    CrossrefPubMedGoogle Scholar
  • 51 Gailhouste L, Gomez-Santos L, Hagiwara K , et al. miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells. Hepatology 2013; 58 (3) 1153-1165
    CrossrefPubMedGoogle Scholar
  • 52 Zhang Z, Zheng W, Hai J. MicroRNA-148b expression is decreased in hepatocellular carcinoma and associated with prognosis. Med Oncol 2014; 31 (6) 984
    CrossrefPubMedGoogle Scholar
  • 53 Zhang Y, Wei W, Cheng N , et al. Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling. Hepatology 2012; 56 (5) 1631-1640
    CrossrefPubMedGoogle Scholar
  • 54 Wang R, Zhao N, Li S , et al. MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology 2013; 58 (2) 642-653
    CrossrefPubMedGoogle Scholar
  • 55 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 (1) 113-121
    CrossrefPubMedGoogle Scholar
  • 56 Tan S, Li R, Ding K, Lobie PE, Zhu T. miR-198 inhibits migration and invasion of hepatocellular carcinoma cells by targeting the HGF/c-MET pathway. FEBS Lett 2011; 585 (14) 2229-2234
    CrossrefPubMedGoogle Scholar
  • 57 Jiang J, Gusev Y, Aderca I , et al. Association of MicroRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 2008; 14 (2) 419-427
    CrossrefPubMedGoogle Scholar
  • 58 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 (12) 5184-5193
    CrossrefPubMedGoogle Scholar
  • 59 Zhang L, Yang F, Yuan JH , et al. Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis 2013; 34 (3) 577-586
    CrossrefPubMedGoogle Scholar
  • 60 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 (2) 629-641
    CrossrefPubMedGoogle Scholar
  • 61 Park JK, Kogure T, Nuovo GJ , et al. miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Res 2011; 71 (24) 7608-7616
    CrossrefPubMedGoogle Scholar
  • 62 Pineau P, Volinia S, McJunkin K , et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A 2010; 107 (1) 264-269
    CrossrefPubMedGoogle Scholar
  • 63 Wong QW, Ching AK, Chan AW , et al. MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling. Clin Cancer Res 2010; 16 (3) 867-875
    CrossrefPubMedGoogle Scholar
  • 64 Yang YF, Wang F, Xiao JJ , et al. MiR-222 overexpression promotes proliferation of human hepatocellular carcinoma HepG2 cells by downregulating p27. Int J Clin Exp Med 2014; 7 (4) 893-902
    PubMedGoogle Scholar
  • 65 Dong YW, Wang R, Cai QQ , et al. Sulfatide epigenetically regulates miR-223 and promotes the migration of human hepatocellular carcinoma cells. J Hepatol 2014; 60 (4) 792-801
    PubMedGoogle Scholar
  • 66 Zhang Y, Takahashi S, Tasaka A, Yoshima T, Ochi H, Chayama K. Involvement of microRNA-224 in cell proliferation, migration, invasion, and anti-apoptosis in hepatocellular carcinoma. J Gastroenterol Hepatol 2013; 28 (3) 565-575
    CrossrefPubMedGoogle Scholar
  • 67 Yu L, Zhang J, Guo X, Li Z, Zhang P. MicroRNA-224 upregulation and AKT activation synergistically predict poor prognosis in patients with hepatocellular carcinoma. Cancer Epidemiol 2014; 38 (4) 408-413
    CrossrefPubMedGoogle Scholar
  • 68 Buurman R, Gürlevik E, Schäffer V , et al. Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 2012; 143 (3) 811-20.e1 , 15
    Google Scholar
  • 69 Fornari F, Milazzo M, Chieco P , et al. 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 (3) 275-285
    CrossrefPubMedGoogle Scholar
  • 70 Guerrieri F, Belloni L, Pediconi N, Levrero M. Molecular mechanisms of HBV-associated hepatocarcinogenesis. Semin Liver Dis 2013; 33 (2) 147-156
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Liu WH, Yeh SH, Chen PJ. Role of microRNAs in hepatitis B virus replication and pathogenesis. Biochim Biophys Acta 2011; 1809 (11–12) 678-685
    CrossrefPubMedGoogle Scholar
  • 72 Liu WH, Yeh SH, Lu CC , et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology 2009; 136 (2) 683-693
    CrossrefPubMedGoogle Scholar
  • 73 Zhang X, Zhang E, Ma Z , et al. Modulation of hepatitis B virus replication and hepatocyte differentiation by MicroRNA-1. Hepatology 2011; 53 (5) 1476-1485
    CrossrefPubMedGoogle Scholar
  • 74 Vezali E, Aghemo A, Colombo M. A review of the treatment of chronic hepatitis C virus infection in cirrhosis. Clin Ther 2010; 32 (13) 2117-2138
    CrossrefPubMedGoogle Scholar
  • 75 Rehm J, Taylor B, Mohapatra S , et al. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev 2010; 29 (4) 437-445
    CrossrefPubMedGoogle Scholar
  • 76 Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002; 31 (4) 339-346
    CrossrefPubMedGoogle Scholar
  • 77 Ozen C, Yildiz G, Dagcan AT , et al. Genetics and epigenetics of liver cancer. New Biotechnol 2013; 30 (4) 381-384
    CrossrefPubMedGoogle Scholar
  • 78 Wang B, Majumder S, Nuovo G , et al. Role of microRNA-155 at early stages of hepatocarcinogenesis induced by choline-deficient and amino acid-defined diet in C57BL/6 mice. Hepatology 2009; 50 (4) 1152-1161
    CrossrefPubMedGoogle Scholar
  • 79 Perkel JM. Visiting “noncodarnia”. Biotechniques 2013; 54 (6) 301-304 , 303–304
    PubMedGoogle Scholar
  • 80 Li CH, Chen Y. Targeting long non-coding RNAs in cancers: progress and prospects. Int J Biochem Cell Biol 2013; 45 (8) 1895-1910
    CrossrefPubMedGoogle Scholar
  • 81 Mercer TR, Dinger ME, Mattick JS. Long non-coding RNAs: insights into functions. Nat Rev Genet 2009; 10 (3) 155-159
    CrossrefPubMedGoogle Scholar
  • 82 Derrien T, Johnson R, Bussotti G , et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 2012; 22 (9) 1775-1789
    CrossrefPubMedGoogle Scholar
  • 83 Yan B, Wang ZH, Guo JT. The research strategies for probing the function of long noncoding RNAs. Genomics 2012; 99 (2) 76-80
    CrossrefPubMedGoogle Scholar
  • 84 Takahashi K, Yan IK, Haga H, Patel T. Modulation of hypoxia-signaling pathways by extracellular linc-RoR. J Cell Sci 2014; 127 (Pt 7): 1585-1594
    CrossrefPubMedGoogle Scholar
  • 85 Zhao Y, Guo Q, Chen J, Hu J, Wang S, Sun Y. Role of long non-coding RNA HULC in cell proliferation, apoptosis and tumor metastasis of gastric cancer: a clinical and in vitro investigation. Oncol Rep 2014; 31 (1) 358-364
    PubMedGoogle Scholar
  • 86 Xie H, Ma H, Zhou D. Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma. Biomed Res Int 2013; 2013: 136106
    PubMedGoogle Scholar
  • 87 Hämmerle M, Gutschner T, Uckelmann H , et al. Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1). Hepatology 2013; 58 (5) 1703-1712
    CrossrefPubMedGoogle Scholar
  • 88 Du Y, Kong G, You X , et al. Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J Biol Chem 2012; 287 (31) 26302-26311
    CrossrefPubMedGoogle Scholar
  • 89 Wang J, Liu X, Wu H , et al. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res 2010; 38 (16) 5366-5383
    CrossrefPubMedGoogle Scholar
  • 90 He Y, Meng XM, Huang C , et al. Long noncoding RNAs: novel insights into hepatocellular carcinoma. Cancer Lett 2014; 344 (1) 20-27
    CrossrefPubMedGoogle Scholar
  • 91 Yang F, Zhang L, Huo XS , et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans. Hepatology 2011; 54 (5) 1679-1689
    CrossrefPubMedGoogle Scholar
  • 92 Anwar SL, Krech T, Hasemeier B , et al. Loss of imprinting and allelic switching at the DLK1-MEG3 locus in human hepatocellular carcinoma. PLoS ONE 2012; 7 (11) e49462
    CrossrefPubMedGoogle Scholar
  • 93 Braconi C, Kogure T, Valeri N , et al. microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 2011; 30 (47) 4750-4756
    CrossrefPubMedGoogle Scholar
  • 94 Nie FQ, Zhu Q, Xu TP , et al. Long non-coding RNA MVIH indicates a poor prognosis for non-small cell lung cancer and promotes cell proliferation and invasion. Tumour Biol 2014; 35 (8) 7587-7594
    CrossrefPubMedGoogle Scholar
  • 95 Yuan SX, Yang F, Yang Y , et al. Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients' poor recurrence-free survival after hepatectomy. Hepatology 2012; 56 (6) 2231-2241
    CrossrefPubMedGoogle Scholar
  • 96 Tsang WP, Wong TW, Cheung AH, Co CN, Kwok TT. Induction of drug resistance and transformation in human cancer cells by the noncoding RNA CUDR. RNA 2007; 13 (6) 890-898
    CrossrefPubMedGoogle Scholar
  • 97 Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett 2013; 339 (2) 159-166
    Google Scholar
  • 98 Lv J, Yu YQ, Li SQ, Luo L, Wang Q. Aflatoxin B1 promotes cell growth and invasion in hepatocellular carcinoma HepG2 cells through H19 and E2F1. Asian Pac J Cancer Prev 2014; 15 (6) 2565-2570
    CrossrefPubMedGoogle Scholar
  • 99 Tsang WP, Kwok TT. Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene 2007; 26 (33) 4877-4881
    CrossrefPubMedGoogle Scholar
  • 100 Gabory A, Jammes H, Dandolo L. The H19 locus: role of an imprinted non-coding RNA in growth and development. BioEssays 2010; 32 (6) 473-480
    CrossrefPubMedGoogle Scholar
  • 101 Iizuka N, Oka M, Yamada-Okabe H , et al. Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 2002; 62 (14) 3939-3944
    PubMedGoogle Scholar
  • 102 Ariel I, Miao HQ, Ji XR , et al. Imprinted H19 oncofetal RNA is a candidate tumour marker for hepatocellular carcinoma. Mol Pathol 1998; 51 (1) 21-25
    CrossrefPubMedGoogle Scholar
  • 103 Geng YJ, Xie SL, Li Q, Ma J, Wang GY. Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression. J Int Med Res 2011; 39 (6) 2119-2128
    CrossrefPubMedGoogle Scholar
  • 104 Yang Z, Zhou L, Wu LM , et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol 2011; 18 (5) 1243-1250
    CrossrefPubMedGoogle Scholar
  • 105 Ishibashi M, Kogo R, Shibata K , et al. Clinical significance of the expression of long non-coding RNA HOTAIR in primary hepatocellular carcinoma. Oncol Rep 2013; 29 (3) 946-950
    PubMedGoogle Scholar
  • 106 Ding C, Cheng S, Yang Z , et al. Long non-coding RNA HOTAIR promotes cell migration and invasion via down-regulation of RNA binding motif protein 38 in hepatocellular carcinoma cells. Int J Mol Sci 2014; 15 (3) 4060-4076
    CrossrefPubMedGoogle Scholar
  • 107 Quagliata L, Matter MS, Piscuoglio S , et al. Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology 2014; 59 (3) 911-923
    CrossrefPubMedGoogle Scholar
  • 108 Lai MC, Yang Z, Zhou L , et al. Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol 2012; 29 (3) 1810-1816
    CrossrefPubMedGoogle Scholar
  • 109 Lin R, Maeda S, Liu C, Karin M, Edgington TS. A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 2007; 26 (6) 851-858
    CrossrefPubMedGoogle Scholar
  • 110 Takahashi K, Yan IK, Kogure T, Haga H, Patel T. Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio 2014; 4: 458-467
    CrossrefPubMedGoogle Scholar
  • 111 Hou P, Zhao Y, Li Z , et al. LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis. Cell Death Dis 2014; 5: e1287
    CrossrefPubMedGoogle Scholar
  • 112 Yuan JH, Yang F, Wang F , et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 2014; 25 (5) 666-681
    CrossrefPubMedGoogle Scholar
  • 113 Takahashi K, Yan I, Haga H, Patel T. Long noncoding RNA in liver diseases. Hepatology 2014; 60 (2) 744-753
    CrossrefPubMedGoogle Scholar
  • 114 Carninci P, Kasukawa T, Katayama S , et al; FANTOM Consortium; RIKEN Genome Exploration Research Group and Genome Science Group (Genome Network Project Core Group). The transcriptional landscape of the mammalian genome. Science 2005; 309 (5740) 1559-1563
    CrossrefPubMedGoogle Scholar
  • 115 Guttman M, Amit I, Garber M , et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 2009; 458 (7235) 223-227
    CrossrefPubMedGoogle Scholar
  • 116 Wang Z, Li X. The role of noncoding RNA in hepatocellular carcinoma. Gland Surg 2013; 2 (1) 25-29
    PubMedGoogle Scholar
  • 117 Panzitt K, Tschernatsch MM, Guelly C , et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 2007; 132 (1) 330-342
    CrossrefPubMedGoogle Scholar
  • 118 Bejerano G, Pheasant M, Makunin I , et al. Ultraconserved elements in the human genome. Science 2004; 304 (5675) 1321-1325
    CrossrefPubMedGoogle Scholar
  • 119 Calin GA, Liu CG, Ferracin M , et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 2007; 12 (3) 215-229
    CrossrefPubMedGoogle Scholar
  • 120 Mestdagh P, Fredlund E, Pattyn F , et al. An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours. Oncogene 2010; 29 (24) 3583-3592
    CrossrefPubMedGoogle Scholar
  • 121 Kogure T, Yan IK, Lin WL, Patel T. Extracellular vesicle-mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer. Genes Cancer 2013; 4 (7–8) 261-272
    CrossrefPubMedGoogle Scholar
  • 122 Li W, Xie L, He X , et al. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. Int J Cancer 2008; 123 (7) 1616-1622
    CrossrefPubMedGoogle Scholar
  • 123 Borel F, Konstantinova P, Jansen PL. Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma. J Hepatol 2012; 56 (6) 1371-1383
    PubMedGoogle Scholar
  • 124 Hou W, Bonkovsky HL. Non-coding RNAs in hepatitis C-induced hepatocellular carcinoma: dysregulation and implications for early detection, diagnosis and therapy. World J Gastroenterol 2013; 19 (44) 7836-7845
    CrossrefPubMedGoogle Scholar
  • 125 Xiao F, Zhang W, Zhou L , et al. microRNA-200a is an independent prognostic factor of hepatocellular carcinoma and induces cell cycle arrest by targeting CDK6. Oncol Rep 2013; 30 (5) 2203-2210
    PubMedGoogle Scholar
  • 126 Lv Z, Wei Y, Wang D, Zhang CY, Zen K, Li L. Argonaute 2 in cell-secreted microvesicles guides the function of secreted miRNAs in recipient cells. PLoS ONE 2014; 9 (7) e103599
    CrossrefPubMedGoogle Scholar
  • 127 Cereghetti DM, Lee PP. Tumor-derived exosomes contain microRNAs with immunological function: implications for a novel immunosuppression mechanism. Microrna 2014; 2 (3) 194-204
    CrossrefPubMedGoogle Scholar
  • 128 Kogure T, Lin WL, Yan IK, Braconi C, Patel T. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 2011; 54 (4) 1237-1248
    CrossrefPubMedGoogle Scholar
  • 129 Diaz G, Melis M, Tice A , et al. Identification of microRNAs specifically expressed in hepatitis C virus-associated hepatocellular carcinoma. Int J Cancer 2013; 133 (4) 816-824
    CrossrefPubMedGoogle Scholar
  • 130 Varnholt H, Drebber U, Schulze F , et al. MicroRNA gene expression profile of hepatitis C virus-associated hepatocellular carcinoma. Hepatology 2008; 47 (4) 1223-1232
    CrossrefPubMedGoogle Scholar
  • 131 Abdalla MA, Haj-Ahmad Y. Promising candidate urinary microrna biomarkers for the early detection of hepatocellular carcinoma among high-risk hepatitis C virus Egyptian patients. J Cancer 2012; 3: 19-31
    CrossrefPubMedGoogle Scholar
  • 132 Fu Y, Wei X, Tang C , et al. Circulating microRNA-101 as a potential biomarker for hepatitis B virus-related hepatocellular carcinoma. Oncol Lett 2013; 6 (6) 1811-1815
    PubMedGoogle Scholar
  • 133 Hou J, Lin L, Zhou W , et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 2011; 19 (2) 232-243
    CrossrefPubMedGoogle Scholar
  • 134 Karakatsanis A, Papaconstantinou I, Gazouli M, Lyberopoulou A, Polymeneas G, Voros D. Expression of microRNAs, miR-21, miR-31, miR-122, miR-145, miR-146a, miR-200c, miR-221, miR-222, and miR-223 in patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma and its prognostic significance. Mol Carcinog 2013; 52 (4) 297-303
    CrossrefPubMedGoogle Scholar
  • 135 Xie K, Liu J, Zhu L , et al. A potentially functional polymorphism in the promoter region of let-7 family is associated with survival of hepatocellular carcinoma. Cancer Epidemiol 2013; 37 (6) 998-1002
    CrossrefPubMedGoogle Scholar
  • 136 Xu Y, Liu L, Liu J , et al. A potentially functional polymorphism in the promoter region of miR-34b/c is associated with an increased risk for primary hepatocellular carcinoma. Int J Cancer 2011; 128 (2) 412-417
    CrossrefPubMedGoogle Scholar
  • 137 Liang TJ, Liu HJ, Zhao XQ, Yu CH, Li CS. Lack of association of MiR-34b/c polymorphism (rs4938723) with hepatocellular carcinoma: a meta-analysis. PLoS ONE 2013; 8 (7) e68588
    CrossrefPubMedGoogle Scholar
  • 138 Son MS, Jang MJ, Jeon YJ , et al. Promoter polymorphisms of pri-miR-34b/c are associated with hepatocellular carcinoma. Gene 2013; 524 (2) 156-160
    CrossrefPubMedGoogle Scholar
  • 139 Tao T, Chen S, Xu B , et al. Association between hsa-miR-34b/c rs4938723 T > C promoter polymorphism and cancer risk: a meta-analysis based on 6,036 cases and 6,204 controls. Chin J Cancer Res 2014; 26 (3) 315-322
    PubMedGoogle Scholar
  • 140 Bae JS, Kim JH, Pasaje CF , et al. Association study of genetic variations in microRNAs with the risk of hepatitis B-related liver diseases. Dig Liver Dis 2012; 44 (10) 849-854
    CrossrefPubMedGoogle Scholar
  • 141 Liu Y, Zhang Y, Wen J , et al. A genetic variant in the promoter region of miR-106b-25 cluster and risk of HBV infection and hepatocellular carcinoma. PLoS ONE 2012; 7 (2) e32230
    CrossrefPubMedGoogle Scholar
  • 142 Qi F, Huang M, Pan Y , et al. A genetic variant in the promoter region of miR-106b-25 cluster predict clinical outcome of HBV-related hepatocellular carcinoma in Chinese. PLoS ONE 2014; 9 (1) e85394
    CrossrefPubMedGoogle Scholar
  • 143 Akkız H, Bayram S, Bekar A, Akgöllü E, Usküdar O, Sandıkçı M. No association of pre-microRNA-146a rs2910164 polymorphism and risk of hepatocellular carcinoma development in Turkish population: a case-control study. Gene 2011; 486 (1–2) 104-109
    CrossrefPubMedGoogle Scholar
  • 144 Xiang Y, Fan S, Cao J, Huang S, Zhang LP. Association of the microRNA-499 variants with susceptibility to hepatocellular carcinoma in a Chinese population. Mol Biol Rep 2012; 39 (6) 7019-7023
    CrossrefPubMedGoogle Scholar
  • 145 Zhou B, Dong LP, Jing XY , et al. Association between miR-146aG>C and miR-196a2C>T polymorphisms and the risk of hepatocellular carcinoma in a Chinese population. Tumour Biol 2014; 35 (8) 7775-7780
    CrossrefPubMedGoogle Scholar
  • 146 Kim WH, Min KT, Jeon YJ , et al. Association study of microRNA polymorphisms with hepatocellular carcinoma in Korean population. Gene 2012; 504 (1) 92-97
    CrossrefPubMedGoogle Scholar
  • 147 Kou JT, Fan H, Han D , et al. Association between four common microRNA polymorphisms and the risk of hepatocellular carcinoma and HBV infection. Oncol Lett 2014; 8 (3) 1255-1260
    PubMedGoogle Scholar
  • 148 Wang XH, Wang FR, Tang YF, Zou HZ, Zhao YQ. Association of miR-149C>T and miR-499A>G polymorphisms with the risk of hepatocellular carcinoma in the Chinese population. Genet Mol Res 2014; 13 (3) 5048-5054
    CrossrefPubMedGoogle Scholar
  • 149 Li XD, Li ZG, Song XX, Liu CF. A variant in microRNA-196a2 is associated with susceptibility to hepatocellular carcinoma in Chinese patients with cirrhosis. Pathology 2010; 42 (7) 669-673
    CrossrefPubMedGoogle Scholar
  • 150 Akkız H, Bayram S, Bekar A, Akgöllü E, Ulger Y. A functional polymorphism in pre-microRNA-196a-2 contributes to the susceptibility of hepatocellular carcinoma in a Turkish population: a case-control study. J Viral Hepat 2011; 18 (7) e399-e407
    CrossrefPubMedGoogle Scholar
  • 151 Guo J, Jin M, Zhang M, Chen K. A genetic variant in miR-196a2 increased digestive system cancer risks: a meta-analysis of 15 case-control studies. PLoS ONE 2012; 7 (1) e30585
    CrossrefPubMedGoogle Scholar
  • 152 Kim HY, Yoon JH, Lee HS , et al. MicroRNA-196A-2 polymorphisms and hepatocellular carcinoma in patients with chronic hepatitis B. J Med Virol 2014; 86 (3) 446-453
    CrossrefPubMedGoogle Scholar
  • 153 Kwak MS, Lee DH, Cho Y , et al. Association of polymorphism in pri-microRNAs-371-372-373 with the occurrence of hepatocellular carcinoma in hepatitis B virus infected patients. PLoS ONE 2012; 7 (7) e41983
    CrossrefPubMedGoogle Scholar
  • 154 Akkiz H, Bayram S, Bekar A, Akgöllü E, Üsküdar O. Genetic variation in the microRNA-499 gene and hepatocellular carcinoma risk in a Turkish population: lack of any association in a case-control study. Asian Pac J Cancer Prev 2011; 12 (11) 3107-3112
    PubMedGoogle Scholar
  • 155 Liu Y, Pan S, Liu L , et al. A genetic variant in long non-coding RNA HULC contributes to risk of HBV-related hepatocellular carcinoma in a Chinese population. PLoS ONE 2012; 7 (4) e35145
    CrossrefPubMedGoogle Scholar
  • 156 Cheetham SW, Gruhl F, Mattick JS, Dinger ME. Long noncoding RNAs and the genetics of cancer. Br J Cancer 2013; 108 (12) 2419-2425
    CrossrefPubMedGoogle Scholar
  • 157 Braconi C, Patel T. Non-coding RNAs as therapeutic targets in hepatocellular cancer. Curr Cancer Drug Targets 2012; 12 (9) 1073-1080
    PubMedGoogle Scholar
  • 158 Chen Z, Ma T, Huang C , et al. MicroRNA-148a: a potential therapeutic target for cancer. Gene 2014; 533 (1) 456-457
    CrossrefPubMedGoogle Scholar
  • 159 D'Anzeo M, Faloppi L, Scartozzi M , et al. The role of micro-RNAs in hepatocellular carcinoma: from molecular biology to treatment. Molecules 2014; 19 (5) 6393-6406
    CrossrefPubMedGoogle Scholar
  • 160 Tomimaru Y, Eguchi H, Nagano H , et al. MicroRNA-21 induces resistance to the anti-tumour effect of interferon-α/5-fluorouracil in hepatocellular carcinoma cells. Br J Cancer 2010; 103 (10) 1617-1626
    CrossrefPubMedGoogle Scholar
  • 161 Henke JI, Goergen D, Zheng J , et al. microRNA-122 stimulates translation of hepatitis C virus RNA. EMBO J 2008; 27 (24) 3300-3310
    CrossrefPubMedGoogle Scholar
  • 162 Lanford RE, Hildebrandt-Eriksen ES, Petri A , et al. Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 2010; 327 (5962): 198-201
    CrossrefPubMedGoogle Scholar
  • 163 Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007; 4 (9) 721-726
    CrossrefPubMedGoogle Scholar
  • 164 Sun BS, Dong QZ, Ye QH , et al. Lentiviral-mediated miRNA against osteopontin suppresses tumor growth and metastasis of human hepatocellular carcinoma. Hepatology 2008; 48 (6) 1834-1842
    CrossrefPubMedGoogle Scholar