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Role of non-coding RNAs in liver disease progression to hepatocellular carcinoma

  • Mi Jeong Heo
  • Jessica Yun
  • Sang Geon KimEmail author
Review
  • 157 Downloads

Abstract

Hepatocellular carcinoma (HCC) is a tumor with poor prognosis and frequently aggressive. The development of HCC is associated with fibrosis and cirrhosis, which mainly results from nonalcoholic fatty liver disease, excessive alcohol consumption, and viral infections. Non-coding RNAs (ncRNAs) are RNAs transcribed from the genome, but are not translated into proteins. Recently, ncRNAs emerged as key contributors to tumor development and progression because of their abilities to regulate various targets and modulate cell proliferation, differentiation, apoptosis, and development. In this review, we summarize the frequently activated pathways in HCC and discuss the pathological implications of ncRNAs in the context of human liver disease progression, in particular HCC development and progression. This review aims to summarize the role of ncRNA dysregulation in the diseases and discuss the diagnostic and therapeutic potentials of ncRNAs.

Keywords

Hepatocellular carcinoma microRNA Long non-coding RNA Non-coding RNA 

Notes

Acknowledgements

This research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2015M3A9B6074045).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Amicone L, Terradillos O, Calvo L, Costabile B, Cicchini C, Della Rocca C, Lozupone F, Piacentini M, Buendia MA, Tripodi M (2002) Synergy between truncated c-Met (cyto-Met) and c-Myc in liver oncogenesis: importance of TGF-beta signalling in the control of liver homeostasis and transformation. Oncogene 21:1335–1345CrossRefPubMedGoogle Scholar
  2. Anson M, Crain-Denoyelle AM, Baud V, Chereau F, Gougelet A, Terris B, Yamagoe S, Colnot S, Viguier M, Perret C, Couty JP (2012) Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest 2:586–599CrossRefGoogle Scholar
  3. Atanasovska B, Rensen SS, van der Sijde MR, Marsman G, Kumar V, Jonkers I, Withoff S, Shiri-Sverdlov R, Greve JWM, Faber KN, Moshage H, Wijmenga C, van de Sluis B, Hofker MH, Fu J (2017) A liver-specific long noncoding RNA with a role in cell viability is elevated in human nonalcoholic steatohepatitis. Hepatology 3:794–808CrossRefGoogle Scholar
  4. Baffy G, Brunt EM, Caldwell SH (2012) Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 6:1384–1391CrossRefGoogle Scholar
  5. Bala S, Marcos M, Kodys K, Csak T, Catalano D, Mandrekar P, Szabo G (2011) Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor alpha (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease. J Biol Chem 2:1436–1444CrossRefGoogle Scholar
  6. Bala S, Csak T, Saha B, Zatsiorsky J, Kodys K, Catalano D, Satishchandran A, Szabo G (2016) The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis. J Hepatol 6:1378–1387CrossRefGoogle Scholar
  7. Bandiera S, Pernot S, El Saghire H, Durand SC, Thumann C, Crouchet E, Ye T, Fofana I, Oudot MA, Barths J, Schuster C, Pessaux P, Heim MH, Baumert TF, Zeisel MB (2016) Hepatitis C Virus-induced upregulation of microRNA miR-146a-5p in hepatocytes promotes viral infection and deregulates metabolic pathways associated with liver disease pathogenesis. J Virol 14:6387–6400CrossRefGoogle Scholar
  8. Bao C, Li Y, Huan L, Zhang Y, Zhao F, Wang Q, Liang L, Ding J, Liu L, Chen T, Li J, Yao M, Huang S, He X (2015) NF-κB signaling relieves negative regulation by miR-194 in hepatocellular carcinoma by suppressing the transcription factor HNF-1α. Sci Signal 387:ra7Google Scholar
  9. Barad O, Meiri E, Avniel A, Aharonov R, Barzilai A, Bentwich I, Einav U, Gilad S, Hurban P, Karov Y, Lobenhofer EK, Sharon E, Shiboleth YM, Shtutman M, Bentwich Z, Einat P (2004) MicroRNA expression detected by oligonucleotide microarrays: system establishment and expression profiling in human tissues. Genome Res 12:2486–2494CrossRefGoogle Scholar
  10. Beg MS, Brenner AJ, Sachdev J, Borad M, Kang YK, Stoudemire J, Smith S, Bader AG, Kim S, Hong DS (2017) Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest New Drugs 35:180–188CrossRefPubMedGoogle Scholar
  11. Bengochea A, de Souza MM, Lefrançois L, Le Roux E, Galy O, Chemin I, Kim M, Wands JR, Trepo C, Hainaut P, Scoazec JY, Vitvitski L, Merle P (2008) Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer 1:143–150CrossRefGoogle Scholar
  12. Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 6818:363–366CrossRefGoogle Scholar
  13. Bertran E, Crosas-Molist E, Sancho P, Caja L, Lopez-Luque J, Navarro E, Egea G, Lastra R, Serrano T, Ramos E, Fabregat I (2013) Overactivation of the TGF-β pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells. Hepatology 58:2032–2044CrossRefPubMedGoogle Scholar
  14. Braconi C, Kogure T, Valeri N, Huang N, Nuovo G, Costinean S, Negrini M, Miotto E, Croce CM, Patel T (2011) microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene 47:4750–4756CrossRefGoogle Scholar
  15. Bugianesi E (2007) Non-alcoholic steatohepatitis and cancer. Clin Liver Dis 11:191–207CrossRefPubMedGoogle Scholar
  16. Callegari E, Elamin BK, Giannone F, Milazzo M, Altavilla G, Fornari F, Giacomelli L, D’Abundo L, Ferracin M, Bassi C, Zagatti B, Corrà F, Miotto E, Lupini L, Bolondi L, Gramantieri L, Croce CM, Sabbioni S, Negrini M (2012) Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology 56:1025–1033CrossRefPubMedGoogle Scholar
  17. Callegari E, D’Abundo L, Guerriero P, Simioni C, Elamin B, Russo M, Cani A, Bassi C, Zagatti B, Giacomelli L, Blandamura S, Moshiri F, Ultimo S, Frassoldati A, Altavilla G, Gramantieri L, Neri L, Sabbioni S, Negrini M (2018) miR-199a-3p Modulates MTOR and PAK4 pathways and inhibits tumor growth in a hepatocellular carcinoma transgenic mouse model. Mol Ther Nucleic Acids 11:485–493CrossRefPubMedPubMedCentralGoogle Scholar
  18. Carnero E, Barriocanal M, Prior C, Pablo Unfried J, Segura V, Guruceaga E, Enguita M, Smerdou C, Gastaminza P, Fortes P (2016) Long noncoding RNA EGOT negatively affects the antiviral response and favors HCV replication. EMBO Rep 7:1013–1028CrossRefGoogle Scholar
  19. Chen DS, Sung JL, Sheu JC, Lai MY, How SW, Hsu HC, Lee CS, Wei TC (1984) Serum alpha-fetoprotein in the early stage of human hepatocellular carcinoma. Gastroenterology 86:1404–1409PubMedGoogle Scholar
  20. Chen Y, Shen A, Rider PJ, Yu Y, Wu K, Mu Y, Hao Q, Liu Y, Gong H, Zhu Y, Liu F, Wu J (2011) A liver-specific microRNA binds to a highly conserved RNA sequence of hepatitis B virus and negatively regulates viral gene expression and replication. FASEB J 25(12):4511–4521CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chen JJ, Tang YS, Huang SF, Ai JG, Wang HX, Zhang LP (2015) HBx protein-induced upregulation of microRNA-221 promotes aberrant proliferation in HBV–related hepatocellular carcinoma by targeting estrogen receptor-α. Oncol Rep 2:792–798CrossRefGoogle Scholar
  22. Chen G, Yu D, Nian X, Liu J, Koenig RJ, Xu B, Sheng L (2016) LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL). Sci Rep 6:35531CrossRefPubMedPubMedCentralGoogle Scholar
  23. Cheng L, Zhu Y, Han H, Zhang Q, Cui K, Shen H, Zhang J, Yan J, Prochownik E, Li Y (2017) MicroRNA-148a deficiency promotes hepatic lipid metabolism and hepatocarcinogenesis in mice. Cell Death Dis 7:e2916CrossRefGoogle Scholar
  24. Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum JM, Min H, Luketic VA, Sanyal AJ (2008) Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 48:1810–1820CrossRefPubMedPubMedCentralGoogle Scholar
  25. Choi Y, Dienes HP, Krawczynski K (2013) Kinetics of miR-122 expression in the liver during acute HCV infection. PLoS ONE 10:e76501CrossRefGoogle Scholar
  26. Coulouarn C, Factor VM, Andersen JB, Durkin ME, Thorgeirsson SS (2009) Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene 40:3526–3536CrossRefGoogle Scholar
  27. Cui M, Xiao Z, Wang Y, Zheng M, Song T, Cai X, Sun B, Ye L, Zhang X (2015) Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway. Cancer Res 5:846–857CrossRefGoogle Scholar
  28. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C (1998) Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95:8847–8851CrossRefGoogle Scholar
  29. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2:117–129CrossRefGoogle Scholar
  30. Dolganiuc A, Petrasek J, Kodys K, Catalano D, Mandrekar P, Velayudham A, Szabo G (2009) MicroRNA expression profile in Lieber-DeCarli diet-induced alcoholic and methionine choline deficient diet-induced nonalcoholic steatohepatitis models in mice. Alcohol Clin Exp Res 10:1704–1710CrossRefGoogle Scholar
  31. Donato F, Tagger A, Chiesa R, Ribero ML, Tomasoni V, Fasola M, Gelatti U, Portera G, Boffetta P, Nardi G (1997) Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: a case-control study in Italy, Brescia HCC Study. Hepatology 26:579–584CrossRefPubMedGoogle Scholar
  32. Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, Decarli A, Trevisi P, Ribero ML, Martelli C, Porru S, Nardi G (2002) Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 4:323–331CrossRefGoogle Scholar
  33. Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Ye L, Zhang X (2012) 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 31:26302–26311CrossRefGoogle Scholar
  34. Du NH, Arpat AB, De Matos M, Gatfield D (2014) MicroRNAs shape circadian hepatic gene expression on a transcriptome-wide scale Elife 3:e02510PubMedGoogle Scholar
  35. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118–1127CrossRefPubMedGoogle Scholar
  36. El-Serag HB (2012) Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 6:1264–1273CrossRefGoogle Scholar
  37. El–Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 7:2557–2576CrossRefGoogle Scholar
  38. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2:87–98CrossRefGoogle Scholar
  39. Faghihi MA, Wahlestedt C (2009) Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol 9:637–643CrossRefGoogle Scholar
  40. Flemming JA, Yang JD, Vittinghoff E, Kim WR, Terrault NA (2014) Risk prediction of hepatocellular carcinoma in patients with cirrhosis: the ADRESS-HCC risk model. Cancer 22:3485–3493CrossRefGoogle Scholar
  41. 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 (2009) MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells. Cancer Res 14:5761–5767CrossRefGoogle Scholar
  42. Fornari F, Pollutri D, Patrizi C, La Bella T, Marinelli S, Casadei Gardini A, Marisi G, Baron Toaldo M, Baglioni M, Salvatore V, Callegari E, Baldassarre M, Galassi M, Giovannini C, Cescon M, Ravaioli M, Negrini M, Bolondi L, Gramantieri L (2017) In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis. Clin Cancer Res 14:3953–3965CrossRefGoogle Scholar
  43. Förstemann K, Horwich MD, Wee L, Tomari Y, Zamore PD (2007) Drosophila microRNAs are sorted into functionally distinct argonaute complexes after production by dicer-1. Cell 2:287–297CrossRefGoogle Scholar
  44. Fransvea E, Mazzocca A, Antonaci S, Giannelli G (2009) Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma. Hepatology 3:839–850CrossRefGoogle Scholar
  45. Friedman RC, Farh KK, Burge CB, Bartel D (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105CrossRefPubMedPubMedCentralGoogle Scholar
  46. 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 (2013) miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells. Hepatology 3:1153–1165CrossRefGoogle Scholar
  47. Gao P, Wong CC, Tung EK, Lee JM, Wong CM, Ng IO (2011) Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis. J Hepatol 54:1177–1184CrossRefPubMedGoogle Scholar
  48. Gao X, Zhao P, Hu J, Zhu H, Zhang J, Zhou Z, Zhao Tang F (2018) MicroRNA-194 protects against chronic hepatitis B-related liver damage by promoting hepatocyte growth via ACVR2B. J Cell Mol Med 9:4534–4544CrossRefGoogle Scholar
  49. Ge Y, Yan X, Jin Y, Yang X, Yu X, Zhou L, Han S, Yuan Q, Yang M (2015) MiRNA-192 and miRNA-204 directly suppress lncRNA HOTTIP and interrupt GLS1-mediated glutaminolysis in hepatocellular carcinoma. PLoS Genet 12:e1005726CrossRefGoogle Scholar
  50. Gebert LF, Rebhan MA, Crivelli SE, Denzler R, Stoffel M, Hall J (2014) Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Nucleic Acids Res 42:609–621CrossRefPubMedGoogle Scholar
  51. Geisler S, Coller J (2013) RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 11:699–712CrossRefGoogle Scholar
  52. Goyal L, Muzumdar MD, Zhu AX (2013) Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res 19:2310–2318CrossRefPubMedPubMedCentralGoogle Scholar
  53. Grabinski N, Ewald F, Hofmann BT, Staufer K, Schumacher U, Nashan B, Jücker M (2012) Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells. Mol Cancer 11:85CrossRefPubMedPubMedCentralGoogle Scholar
  54. Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240CrossRefPubMedGoogle Scholar
  55. Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN (2004) The Drosha-DGCR8 complex in primary microRNA processing. Genes Dev 18:3016–3027CrossRefPubMedPubMedCentralGoogle Scholar
  56. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ (2002) Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 5:1206–1213CrossRefGoogle Scholar
  57. He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512CrossRefPubMedGoogle Scholar
  58. He JH, Han ZP, Liu JM, Zhou JB, Zou MX, Lv YB, Li YG, Cao MR (2017) Overexpression of long non-coding RNA MEG3 inhibits proliferation of hepatocellular carcinoma Huh7 cells via negative modulation of miRNA-664. J Cell Biochem 11:3713–3721CrossRefGoogle Scholar
  59. Heldin CH, Miyazono K, ten Dijke P (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 6659:465–471CrossRefGoogle Scholar
  60. Heo MJ, Kim YM, Koo JH, Yang YM, An J, Lee SK, Lee SJ, Kim KM, Park JW, Kim SG (2014) microRNA-148a dysregulation discriminates poor prognosis of hepatocellular carcinoma in association with USP4 overexpression. Oncotarget 9:2792–2806Google Scholar
  61. Heo MJ, Kim TH, You JS, Blaya D, Sancho-Bru P, Kim SG (2018) Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression. Gut.  https://doi.org/10.1136/gutjnl-2017-315123 CrossRefPubMedGoogle Scholar
  62. Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, Tian W, Zhang Q, Wang C, Zhang Q, Zhuang SM, Zheng L, Liang A, Tao W, Cao X (2011) Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell 2:232–243CrossRefGoogle Scholar
  63. Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, Yu L, Bai S, La Perle K, Chivukula RR, Mao H, Wei M, Clark KR, Mendell JR, Caligiuri MA, Jacob ST, Mendell JT, Ghoshal K (2012) Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 8:2871–2883CrossRefGoogle Scholar
  64. Hu J, Dong A, Fernandez-Ruiz V, Shan J, Kawa M, Martínez-Ansó E, Prieto J, Qian C (2009) Blockade of Wnt signaling inhibits angiogenesis and tumor growth in hepatocellular carcinoma. Cancer Res 17:6951–6959CrossRefGoogle Scholar
  65. Hu J, Xu Y, Hao J, Wang S, Li C, Meng S (2012) MiR-122 in hepatic function and liver diseases. Protein Cell 5:364–371CrossRefGoogle Scholar
  66. Hutvágner G, McLachlan J, Pasquinelli AE, Bálint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 5531:834–838CrossRefGoogle Scholar
  67. Ishiki Y, Ohnishi H, Muto Y, Matsumoto K, Nakamura T (1992) Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology 16:1227–1235PubMedGoogle Scholar
  68. Jang SY, Kim G, Park SY, Lee YR, Kwon SH, Kim HS, Yoon JS, Lee JS, Kweon Y, Ha HT, Chum JM, Han YS, Lee WK, Chang JY, Park JG, Lee B, Tak WY, Hur K (2017) Clinical significance of lncRNA-ATB expression in human hepatocellular carcinoma. Oncotarget 45:78588–78597Google Scholar
  69. Jangra RK, Yi M, Lemon SM (2010) Regulation of hepatitis C virus translation and infectious virus production by the microRNA miR-122. J Virol 13:6615–6625CrossRefGoogle Scholar
  70. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA, Hodges MR (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 18:1685–1694CrossRefGoogle Scholar
  71. Jin Y, Wang J, Han J, Luo D, Sun Z (2017) MiR-122 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting Snail1 and Snail2 and suppressing WNT/β-cadherin signaling pathway. Exp Cell Res 2:210–217CrossRefGoogle Scholar
  72. Jung HS, Seo YR, Yang YM, Koo JH, An J, Lee SJ, Kim KM, Kim SG (2014) Gα12gep oncogene inhibits FOXO1 in hepatocellular carcinoma as a consequence of miR-135b and miR-194 dysregulation. Cell Signal 7:1456–1465CrossRefGoogle Scholar
  73. Jung KH, Zhang J, Zhou C, Shen H, Gagea M, Rodriguez-Aguayo C, Lopez-Berestein G, Sood AK, Beretta L (2016) Differentiation therapy for hepatocellular carcinoma: multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis. Hepatology 3:864–879CrossRefGoogle Scholar
  74. Kamel MM, Matboli M, Sallam M, Montasser IF, Saad AS, El-Tawdi AHF (2016) Investigation of long noncoding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinoma. Transl Res 168:134–145CrossRefPubMedGoogle Scholar
  75. Katsuno Y, Lamouille S, Derynck R (2013) TGF-β signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol 1:76–84CrossRefGoogle Scholar
  76. Kim YD, Park CH, Kim HS, Choi SK, Rew JS, Kim DY, Koh YS, Jeung KW, Lee KH, Lee JS, Juhng SW, Lee JH (2008) Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma. J Gastroenterol Hepatol 23:110–118CrossRefPubMedGoogle Scholar
  77. Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon YJ, Volinia S, Pineau P, Marchio A, Palatini J, Suh SS, Alder H, Liu CG, Dejean A, Croce CM (2011) p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exp Med 5:875–883CrossRefGoogle Scholar
  78. Kim JH, Lee CH, Lee SW (2016) Hepatitis C virus infection stimulates transforming growth factor-β1 expression through up-regulating miR-192. J Microbiol 54:520CrossRefPubMedGoogle Scholar
  79. Kirstein MM, Boukouris AE, Pothiraju D, Buitrago-Molina LE, Marhenke S, Schutt J, Orlik J, Kuhnel F, Hegermann J, Manns MP, Vogel A (2013) Activity of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in hepatocellular carcinoma. Liver Int. 33:780–793CrossRefPubMedGoogle Scholar
  80. 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 (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137:1005–1017CrossRefPubMedPubMedCentralGoogle Scholar
  81. Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 7068:685–689CrossRefGoogle Scholar
  82. Krützfeldt J, Rösch N, Hausser J, Manoharan M, Zavolan M, Stoffel M (2012) MicroRNA-194 is a target of transcription factor 1 (Tcf1, HNF1α) in adult liver and controls expression of frizzled-6. Hepatology 1:98–107CrossRefGoogle Scholar
  83. Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W, Jacob ST, Ghoshal K (2006) Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem 3:671–678CrossRefGoogle Scholar
  84. Landthaler M, Yalcin A, Tuschl T (2004) The human DiGeorge syndrome critical region gene 8 and its D. melanogaster homolog are required for miRNA biogenesis. Curr Biol 23:2162–2167CrossRefGoogle Scholar
  85. Lee Y, Jeon K, Lee JT, Kim S, Kim VN (2002) MicroRNA maturation: stepwise processing and subcellular localization. EMBO J 17:4663–4670CrossRefGoogle Scholar
  86. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 6956:415–419CrossRefGoogle Scholar
  87. Li S, Chen X, Zhang H, Liang X, Xiang Y, Yu C, Zen K, Li Y, Zhang CY (2009) Differential expression of microRNAs in mouse liver under aberrant energy metabolic status. J Lipid Res 9:1756–1765CrossRefGoogle Scholar
  88. Li J, Wang Y, Yu W, Chen J, Luo J (2011) Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance. Biochem Biophys Res Commun 1:70–73CrossRefGoogle Scholar
  89. Li P, Ruan X, Yang L, Kiesewetter K, Zhao Y, Luo H, Chen Y, Gucek M, Zhu J, Cao H (2015) A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab 3:455–467CrossRefGoogle Scholar
  90. Li SP, Xu HX, Yu Y, He JD, Wang Z, Xu YJ, Wang CY, Zhang HM, Zhang RX, Zhang JJ, Yao Z, Shen ZY (2016a) LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway. Oncotarget 27:42431–42446Google Scholar
  91. Li T, Xie J, Shen C, Cheng D, Shi Y, Wu Z, Deng X, Chen H, Shen B, Peng C, Li H, Zhan Q, Zhu Z (2016b) Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma. Oncogene 12:1575–1584CrossRefGoogle Scholar
  92. Li Z, Gu X, Hu J, Ping Y, Li H, Yan JY, Li J, Sun R, Yu ZJ, Zhang Y (2016c) Hepatitis C virus core protein impairs metabolic disorder of liver cell via HOTAIR-Sirt1 signalling. Biosci Rep 3:e00336CrossRefGoogle Scholar
  93. Li M, He Y, Zhou Z, Ramirez T, Gao Y, Gao Y, Ross RA, Cao H, Cai Y, Xu M, Feng D, Zhang P, Liangpunsakul S, Gao B (2017) MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils. Gut 4:705–715CrossRefGoogle Scholar
  94. Lian J, Jing Y, Dong Q, Huan L, Chen D, Bao C, Wang Q, Zhao F, Li J, Yao M, Qin L, Liang L, He X (2016) miR-192, a prognostic indicator, targets the SLC39A6/SNAIL pathway to reduce tumor metastasis in human hepatocellular carcinoma. Oncotarget 3:2672–2683Google Scholar
  95. Liang WC, Ren JL, Wong CW, Chan SO, Waye MM, Fu WM, Zhang JF (2018) LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling. Oncogene 11:1445–1456CrossRefGoogle Scholar
  96. Lin Y, Ding D, Huang Q, Liu Q, Lu H, Lu Y, Chi Y, Sun X, Ye G, Zhu H, Wei J, Dong S (2017) Downregulation of miR-192 causes hepatic steatosis and lipid accumulation by inducing SREBF1: novel mechanism for bisphenol A-triggered non-alcoholic fatty liver disease. Biochim Biophys Acta Mol Cell Biol Lipids 9:869–882CrossRefGoogle Scholar
  97. Liu AM, Yao T, Wang W (2012a) Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study. BMJ Open 2:e000825CrossRefPubMedPubMedCentralGoogle Scholar
  98. 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 (2012b) MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma. J Hepatol 2:389–396CrossRefGoogle Scholar
  99. Liu XL, Cao HX, Wang BC, Xin FZ, Zhang RN, Zhou D, Yang RX, Zhao ZH, Pan Q, Fan JG (2017) miR-192-5p regulates lipid synthesis in non-alcoholic fatty liver disease through SCD-1. World J Gastroenterol 46:8140–8151CrossRefGoogle Scholar
  100. Lou G, Song X, Yang F, Wu S, Wang J, Chen Z, Liu Y (2015) Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 29:122CrossRefGoogle Scholar
  101. Lu Z, Xiao Z, Liu F, Cui M, Li W, Yang Z, Li J, Ye L, Zhang X (2016) Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1). Oncotarget 1:241–254Google Scholar
  102. Malakar P, Shilo A, Mogilevsky A, Stein I, Pikarsky E, Nevo Y, Benyamini H, Elgavish S, Zong X, Prasanth KV, Karni R (2017) Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation. Cancer Res 5:1155–1167CrossRefGoogle Scholar
  103. Marcellin P, Asselah T, Boyer N (2002) Fibrosis and disease progression in hepatitis C. Hepatology 36:s47–s56PubMedGoogle Scholar
  104. Marquez RT, Bandyopadhyay S, Wendlandt EB, Keck K, Hoffer BA, Icardi MS, Christensen RN, Schmidt WN, McCaffrey AP (2010) Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans. Lab Invest 90:1727–1736CrossRefPubMedGoogle Scholar
  105. Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS (2002) NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36:1349–1354CrossRefPubMedGoogle Scholar
  106. Masuda M, Shimomura M, Kobayashi K, Kojima S, Nakatsura T (2011) Growth inhibition by NVP-BEZ235, a dual PI3 K/mTOR inhibitor, in hepatocellular carcinoma cell lines. Oncol Rep 26:1273–1279PubMedGoogle Scholar
  107. Meng Z, Fu X, Chen X, Zeng S, Tian Y, Jove R, Xu R, Huang W (2010) miR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice. Hepatology 52:2148–2157CrossRefPubMedPubMedCentralGoogle Scholar
  108. Mercer TR, Dinger ME, Mattick JS (2009) Long non-coding RNAs: insights into functions. Nat Rev Genet 3:155–159CrossRefGoogle Scholar
  109. Nassirpour R, Mehta PP, Yin MJ (2013) miR-122 regulates tumorigenesis in hepatocellular carcinoma by targeting AKT3. PLoS ONE 11:e79655CrossRefGoogle Scholar
  110. Nhieu JT, Renard CA, Wei Y, Cherqui D, Zafrani ES, Buendia MA (1999) Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol 3:703–710CrossRefGoogle Scholar
  111. Nie H, Song C, Wang D, Cui S, Ren T, Cao Z, Liu Q, Chen Z, Chen X, Zhou Y (2017) MicroRNA-194 inhibition improves dietary-induced non-alcoholic fatty liver disease in mice through targeting on FXR. Biochim Biophys Acta Mol Basis Dis 12:3087–3094CrossRefGoogle Scholar
  112. Nielsen KO, Jacobsen KS, Mirza AH, Winther TN, Størling J, Glebe D, Pociot F, Hogh B (2018) Hepatitis B virus upregulates host microRNAs that target apoptosis-regulatory genes in an in vitro cell model. Exp Cell Res 371:92–103CrossRefPubMedGoogle Scholar
  113. Nishida N, Goel A (2011) Genetic and epigenetic signatures in human hepatocellular carcinoma: a systematic review. Curr Genomics 2:130–137CrossRefGoogle Scholar
  114. Ohno M, Shibata C, Kishikawa T, Yoshikawa T, Takata A, Kojima K, Akanuma M, Kang YJ, Yoshida H, Otsuka M, Koike K (2013) The flavonoid apigenin improves glucose tolerance through inhibition of microRNA maturation in miRNA103 transgenic mice. Sci Rep 3:2553CrossRefPubMedPubMedCentralGoogle Scholar
  115. Panzitt K, Tschernatsch MM, Guelly C, Moustafa T, Stradner M, Strohmaier HM, Buck CR, Denk H, Schroeder R, Trauner M, Zatloukal K (2007) Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 1:330–342CrossRefGoogle Scholar
  116. Parasramka MA, Maji S, Matsuda A, Yan IK, Patel T (2016) Long non-coding RNAs as novel targets for therapy in hepatocellular carcinoma. Pharmacol Ther 161:67–78CrossRefPubMedPubMedCentralGoogle Scholar
  117. Peng C, Wang H, Zhang W, Jie S, Tong Q, Lu M, Yang D (2016) Inhibitory effect of miR-125b on hepatitis C virus core protein-induced TLR2/MyD88 signaling in THP-1 cells. World J Gastroenterol 17:4354–4361CrossRefGoogle Scholar
  118. Peng L, Yuan XQ, Zhang CY, Ye F, Zhou HF, Li WL, Zhang YQ, Pan X, Li GC (2017) High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients. Oncotarget 21:34387–34397Google Scholar
  119. Petruzziello A (2018) Epidemiology of Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) related hepatocellular carcinoma. Open Virol J 12:26–32CrossRefPubMedPubMedCentralGoogle Scholar
  120. Protzer U, Maini M, Knolle P (2012) Living in the liver: hepatic infections. Nat Rev Immunol 3:201–213CrossRefGoogle Scholar
  121. Qian X, Xu C, Zhao P, Qi Z (2016) Long non-coding RNA GAS5 inhibited hepatitis C virus replication by binding viral NS3 protein. Virology 492:155–165CrossRefPubMedGoogle Scholar
  122. Qu KZ, Zhang K, Li H, Afdhal NH, Albitar M (2011) Circulating microRNAs as biomarkers for hepatocellular carcinoma. J Clin Gastroenterol 4:355–360CrossRefGoogle Scholar
  123. Ratziu V, Bonyhay L, Di M, Charlotte F, Cavallaro L, Sayegh-Tainturier MH, Giral P, Grimaldi A, Opolon P, Poynard T (2002) Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 35:1485–1493CrossRefPubMedGoogle Scholar
  124. Roberts APE, Lewis AP, Jopling CL (2011) miR-122 activates hepatitis C virus translation by a specialized mechanism requiring particular RNA components. Nucleic Acids Res 17:7716–7729CrossRefGoogle Scholar
  125. Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M (2004) mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 24:8421–8425CrossRefGoogle Scholar
  126. Satishchandran A, Ambade A, Rao S, Hsueh YC, Iracheta-Vellve A, Tornai D, Lowe P, Gyongyosi B, Li J, Catalano D, Zhong L, Kodys K, Xie J, Bala S, Gao G, Szabo G (2018) MicroRNA 122, regulated by GRLH2, protects livers of mice and patients from ethanol-induced liver disease. Gastroenterology 1:238–252CrossRefGoogle Scholar
  127. Seitz HK, Stickel F (2007) Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 8:599–612CrossRefGoogle Scholar
  128. Sekine S, Ogawa R, Ito R, Hiraoka N, McManus MT, Kanai Y, Hebrok M (2009) Disruption of Dicer1 induces dysregulated fetal gene expression and promotes hepatocarcinogenesis. Gastroenterology 7:2304–2315CrossRefGoogle Scholar
  129. Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, Kasai H (1994) Increased formation of cxidative DNA damage, 8-Hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res 12:3171–3172Google Scholar
  130. Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, Ben-Ze’ev A (1999) The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci 96:5522–5527CrossRefPubMedGoogle Scholar
  131. Slaby O, Laga R, Sedlacek O (2017) Therapeutic targeting of non-coding RNAs in cancer. Biochem J 24:4219–4251CrossRefGoogle Scholar
  132. Song K, Han C, Zhang J, Lu D, Dash S, Feitelson M, Lim K, Wu T (2013) Epigenetic regulation of MicroRNA-122 by peroxisome proliferator activated receptor-gamma and hepatitis b virus X protein in hepatocellular carcinoma cells. Hepatology 5:1681–1692CrossRefGoogle Scholar
  133. Susluer SY, Kayabasi C, Yelken BO, Asik A, Celik D, Okcanoglu TB, Senger SS, Avci CB, Kose S, Gunduz C (2018) Analysis of long non-coding RNA (lncRNA) expression in hepatitis B patients. Bosn J Basic Med Sci 2:150–161Google Scholar
  134. Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS (2010) Non-coding RNAs: regulators of disease. J Pathol 2:126–139CrossRefGoogle Scholar
  135. Tan Y, Ge G, Pan T, Wen D, Gan J (2014) A pilot study of serum microRNAs panel as potential biomarkers for diagnosis of nonalcoholic fatty liver disease. PLoS ONE 8:e105192CrossRefGoogle Scholar
  136. Tang J, Jiang R, Deng L, Zhang X, Wang K, Sun B (2015) Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in hepatocellular carcinoma. Oncotarget 6:4505–4515PubMedPubMedCentralGoogle Scholar
  137. Thorgeirsson SS, Grisham JW (2002) Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 4:339–346CrossRefGoogle Scholar
  138. Tornesello ML, Buonaguro L, Tatangelo F, Botti G, Izzo F, Buonaguro FM (2013) Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics 102:74–83CrossRefPubMedGoogle Scholar
  139. Trajkovski M, Hausser J, Soutschek J, Bhat B, Akin A, Zavolan M, Heim MH, Stoffel M (2011) MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 7353:649–653CrossRefGoogle Scholar
  140. Trebicka J, Anadol E, Elfimova N, Strack I, Roggendorf M, Viazov S, Wedemeyer I, Drebber U, Rockstroh J, Sauerbruch T, Dienes HP, Odenthal M (2013) Hepatic and serum levels of miR-122 after chronic HCV-induced fibrosis. J Hepatol 2:234–239CrossRefGoogle Scholar
  141. Tsai WC, Hsu PW, Lai TC, Chau GY, Lin CW, Chen CM, Lin CD, Liao YL, Wang JL, Chau YP, Hsu MT, Hsiao M, Huang HD, Tsou AP (2009) MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma. Hepatology 5:1571–1582CrossRefGoogle Scholar
  142. Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, Huang Y, Chen HC, Lee CH, Tsai TF, Hsu MT, Wu JC, Huang HD, Shiao MS, Hsiao M, Tsou AP (2012) MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 8:2884–8897CrossRefGoogle Scholar
  143. Tward AD, Jones KD, Yant S, Cheung ST, Fan ST, Chen X, Kay MA, Wang R, Bishop JM (2007) Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A 37:14771–14776CrossRefGoogle Scholar
  144. Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E (1997) Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinoma. Hepatology 4:862–866CrossRefGoogle Scholar
  145. Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, Roayaie S, Minguez B, Sole M, Battiston C, Van Laarhoven S, Fiel MI, Di Feo A, Hoshida Y, Yea S, Toffanin S, Ramos A, Martignetti JA, Mazzaferro V, Bruix J, Waxman S, Schwartz M, Meyerson M, Friedman SL, Llovet JM (2008) Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 6:1972–1983CrossRefGoogle Scholar
  146. Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 6:904–914CrossRefGoogle Scholar
  147. Wang R, Ferrell LD, Faouzi S, Maher JJ, Bishop JM (2001) Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice. J Cell Biol 5:1023–1034CrossRefGoogle Scholar
  148. Wang J, Liu X, Wu H, Ni P, Gu Z, Qiao Y, Chen N, Sun F, Fan Q (2010) CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nuclei Acids Res 16:5366–5383CrossRefGoogle Scholar
  149. Wang S, Qiu L, Yan X, Jin W, Wang Y, Chen L, Wu E, Ye X, Gao GF, Wang F, Chen Y, Duan Z, Meng S (2012) Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G(1) -modulated P53 activity. Hepatology 55(3):730–741CrossRefPubMedGoogle Scholar
  150. Wang B, Hsu SH, Wang X, Kutay H, Bid HK, Yu J, Ganju RK, Jacob ST, Yuneva M, Ghoshal K (2014) Reciprocal regulation of microRNA-122 and c-Myc in hepatocellular cancer: role of E2F1 and transcription factor dimerization partner 2. Hepatology 2:555–566CrossRefGoogle Scholar
  151. Wang K, Guo WX, Li N, Gao CF, Shi J, Tang YF, Shen F, Wu MC, Liu SR, Cheng SQ (2015a) Serum LncRNAs profiles serve as novel potential biomarkers for the diagnosis of HBV-positive hepatocellular carcinoma. PLoS ONE 12:e0144934CrossRefGoogle Scholar
  152. Wang TH, Lin YS, Chen Y, Yeh CT, Huang YL, Hsieh TH, Shieh TM, Hsueh C, Chen TC (2015b) Long non-coding RNA AOC4P suppresses hepatocellular carcinoma metastasis by enhancing vimentin degradation and inhibiting epithelial-mesenchymal transition. Oncotarget 27:23342–23357Google Scholar
  153. Wang T-H, Yu C-C, Lin Y-S, Chen T-C, Yeh C-T, Liang K-H, Shieh T-M, Chen C-Y, Hsueh C (2016) Long noncoding RNA CPS1-IT1 suppresses the metastasis of hepatocellular carcinoma by regulating HIF-1α activity and inhibiting epithelial-mesenchymal transition. Oncotarget 28:43588–43603Google Scholar
  154. 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 (2015) Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int J Cancer 7:1679–1690CrossRefGoogle Scholar
  155. Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 13:1494–1504CrossRefGoogle Scholar
  156. Wong CM, Fan ST, Ng IO (2001) beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 1:134–136Google Scholar
  157. Xie H, Ma H, Zhou D (2013) Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma. Biomed Res Int 2013:136106PubMedPubMedCentralGoogle Scholar
  158. Xin X, Wu M, Meng Q, Wang C, Lu Y, Yang Y, Li X, Zheng Q, Pu H, Gui X, Li T, Li J, Jia S, Lu D (2018) Long noncoding RNA HULC accelerates liver cancer by inhibiting PTEN via autophagycooperation to miR15a. Mol Cancer 1:94CrossRefGoogle Scholar
  159. Xu J, Zhu X, Wu L, Yang R, Yang Z, Wang Q, Wu F (2012) MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/β-catenin pathway. Liver Int 5:752–760CrossRefGoogle Scholar
  160. Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, Zhu Z, Jiao H, Lin J, Jiang K, Ding L, Zhang H, Cheng L, Fu H, Song Y, Jiang Y, Liu J, Wang R, Du N, Ye Q (2013) Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. J Clin Invest 2:630–645Google Scholar
  161. Yan H, Dong X, Zhong X, Ye J, Zhou Y, Yang X, Shen J, Zhang J (2014) Inhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in miR-148a-mediated anti-metastasis of hepatocellular carcinoma. Mol Carcinog 12:960–969Google Scholar
  162. Yang L, Inokuchi S, Roh YS (2003) Transforming Growth Factor–β Signaling in hepatocytes promotes hepatic fibrosis and carcinogenesis in mice with hepatocyte-specific deletion of TAK1. Gastroenterology 5:1042–1054Google Scholar
  163. Yang YM, Lee CG, Koo JH, Kim TH, Lee JM, An J, Kim KM, Kim SG (2015) Gα12 overexpressed in hepatocellular carcinoma reduces microRNA-122 expression via HNF4α inactivation, which causes c-Met induction. Oncotarget 22:19055–19069Google Scholar
  164. Yang Z, Ross RA, Zhao S, Tu W, Liangpunsakul S, Wang L (2017) LncRNA AK054921 and AK128652 are potential serum biomarkers and predictors of patient survival with alcoholic cirrhosis. Hepatol Commun 6:513–523CrossRefGoogle Scholar
  165. Yin H, Hu M, Zhang R, Shen Z, Flatow L, You M (2012) MicroRNA-217 promotes ethanol-induced fat accumulation in hepatocytes by down-regulating SIRT1. J Biol Chem 13:9817–9826CrossRefGoogle Scholar
  166. Yuan K, Lian Z, Sun B, Clayton M, Ng I, Feitelson M (2012) Role of miR-148a in Hepatitis B associated hepatocellular carcinoma. PLoS ONE 4:e35331CrossRefGoogle Scholar
  167. Zarrinpar A, Gupta S, Maurya MR, Subramaniam S, Loomba R (2016) Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study. Gut 65:1546–1554CrossRefPubMedGoogle Scholar
  168. Zeng C, Wang R, Li D, Lin XJ, Wei QK, Yuan Y, Wang Q, Chen W, Zhuang SM (2010) A novel GSK-3 beta-C/EBP alpha-miR-122-insulin-like growth factor 1 receptor regulatory circuitry in human hepatocellular carcinoma. Hepatology 5:1702–1712CrossRefGoogle Scholar
  169. Zeng X, Lin Y, Yin C, Zhang X, Ning BF, Zhang Q, Zhang JP, Qiu L, Qin XR, Chen YX, Xie WF (2011) Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology 6:2036–2047CrossRefGoogle Scholar
  170. Zhang GL, Li YX, Zheng SQ, Liu M, Li X, Tang H (2010) Suppression of hepatitis B virus replication by microRNA-199a-3p and microRNA-210. Antiviral Res 2:169–175CrossRefGoogle Scholar
  171. Zhang ZZ, Liu X, Wang DQ, Teng MK, Niu LW, Huang AL, Liang Z (2011) Hepatitis B virus and hepatocellular carcinoma at the miRNA level. World J Gastroenterol 28:3353–3358CrossRefGoogle Scholar
  172. Zhang JP, Zeng C, Xu L, Gong J, Fang JH, Zhuang SM (2014) MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene 31:4069–4076CrossRefGoogle Scholar
  173. Zhang Y, Wei C, Guo CC, Bi RX, Xie J, Guan DH, Yang CH, Jiang YH (2017) Prognostic value of microRNAs in hepatocellular carcinoma: a meta-analysis. Oncotarget 8:107237–107257PubMedPubMedCentralGoogle Scholar
  174. Zhao Y, Li F, Zhang X, Liu A, Qi J, Cui H, Zhao P (2015) MicroRNA-194 acts as a prognostic marker and inhibits proliferation in hepatocellular carcinoma by targeting MAP4K4. Int J Clin Exp Pathol 10:12446–12454Google Scholar
  175. Zheng C, Liu X, Chen L, Xu Z, Shao J (2017) lncRNAs as prognostic molecular biomarkers in hepatocellular carcinoma: a systematic review and meta-analysis. Oncotarget 35:59638–59647Google Scholar
  176. Zhou L, Huang Y, Li J, Wang Z (2010) The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med Oncol 2:255–261CrossRefGoogle Scholar
  177. Zhuo H, Tang J, Lin Z, Jiang R, Zhang X, Ji J, Wang P, Sun B (2016) The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellularcarcinoma. Mol Carcinog 2:209–219CrossRefGoogle Scholar

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© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.College of Pharmacy and Research Institute of Pharmaceutical SciencesSeoul National UniversitySeoulSouth Korea

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