Source: https://www.nature.com/articles/nrgastro.2017.169?error=cookies_not_supported&code=e2871f40-883f-4359-9893-29a54944a86a
Timestamp: 2019-04-18 21:50:51+00:00

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Chun-Ming Wong is Assistant Professor in the Department of Pathology and Principal Investigator of the State Key Laboratory for Liver Research at The University of Hong Kong, Pokfulam. He received his PhD and postdoctoral training at The University of Hong Kong. His research interests include genetic alterations, epigenetic modifications and non-coding RNA deregulation in liver cancer.
Felice Ho-Ching Tsang is a postdoctoral fellow in the Department of Pathology at The University of Hong Kong, Pokfulam. She completed her PhD training at The University of Hong Kong. Her work focuses on non-coding RNAs in liver cancer.
Irene Oi-Lin Ng is Chair Professor, Loke Yew Professor in Pathology and Head of the Department of Pathology at The University of Hong Kong, Pokfulam. She is also Director of the State Key Laboratory for Liver Research, The University of Hong Kong. She is Chief of Service in the Department of Pathology at Queen Mary Hospital, Pokfulam, Hong Kong. She received her MBBS, MD and PhD degrees at The University of Hong Kong. Her research focuses on understanding the molecular mechanisms of liver carcinogenesis.
Hepatocellular carcinoma (HCC) is a leading lethal malignancy worldwide. However, the molecular mechanisms underlying liver carcinogenesis remain poorly understood. Over the past two decades, overwhelming evidence has demonstrated the regulatory roles of different classes of non-coding RNAs (ncRNAs) in liver carcinogenesis related to a number of aetiologies, including HBV, HCV and NAFLD. Among the ncRNAs, microRNAs, which belong to a distinct class of small ncRNAs, have been proven to play a crucial role in the post-transcriptional regulation of gene expression. Deregulation of microRNAs has been broadly implicated in the inactivation of tumour-suppressor genes and activation of oncogenes in HCC. Modern high-throughput sequencing analyses have unprecedentedly identified a very large number of non-coding transcripts. Divergent groups of long ncRNAs have been implicated in liver carcinogenesis through interactions with DNA, RNA or proteins. Overall, ncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of the ncRNAs in liver carcinogenesis. In this Review, we summarize the common deregulation of small and long ncRNAs in human HCC. We also comprehensively review the pathological roles of ncRNAs in liver carcinogenesis, epithelial-to-mesenchymal transition and HCC metastasis and discuss the potential applications of ncRNAs as diagnostic tools and therapeutic targets in human HCC.
Younossi, Z. M. et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009 . Hepatology 62, 1723–1730 (2015).
Dhanasekaran, R., Limaye, A. & Cabrera, R. Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics . Hepat. Med. 4, 19–37 (2012).
Wong, C. M. & Ng, I. O. Molecular pathogenesis of hepatocellular carcinoma . Liver Int. 28, 160–174 (2008).
Crick, F. H. On protein synthesis . Symp. Soc. Exp. Biol. 12, 138–163 (1958).
Rosenbloom, K. R. et al. ENCODE whole-genome data in the UCSC Genome Browser: update 2012 . Nucleic Acids Res. 40, D912–D917 (2012).
Derrien, T. et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression . Genome Res. 22, 1775–1789 (2012).
Jonas, S. & Izaurralde, E. Towards a molecular understanding of microRNA-mediated gene silencing . Nat. Rev. Genet. 16, 421–433 (2015).
Kozomara, A. & Griffiths-Jones, S. miRBase: annotating high confidence microRNAs using deep sequencing data . Nucleic Acids Res. 42, D68–D73 (2014).
Ha, M. & Kim, V. N. Regulation of microRNA biogenesis . Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).
Kitagawa, N. et al. Downregulation of the microRNA biogenesis components and its association with poor prognosis in hepatocellular carcinoma . Cancer Sci. 104, 543–551 (2013).
Caruso, S. et al. Germline and somatic DICER1 mutations in familial and sporadic liver tumors . J. Hepatol. 66, 734–742 (2017).
Murakami, Y. et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues . Oncogene 25, 2537–2545 (2006).
Jiang, J. et al. Association of microRNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival . Clin. Cancer Res. 14, 419–427 (2008).
Meng, F. et al. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer . Gastroenterology 133, 647–658 (2007).
Pineau, P. et al. miR-221 overexpression contributes to liver tumorigenesis . Proc. Natl Acad. Sci. USA 107, 264–269 (2010).
Wong, Q. W. et al. MiR-222 overexpression confers cell migratory advantages in hepatocellular carcinoma through enhancing AKT signaling . Clin. Cancer Res. 16, 867–875 (2010).
Gramantieri, L. et al. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma . Cancer Res. 67, 6092–6099 (2007).
Liang, L. et al. MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2 . Hepatology 52, 1731–1740 (2010).
Su, H. et al. MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity . Cancer Res. 69, 1135–1142 (2009).
Wang, Y. et al. Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3 . J. Hepatol. 53, 57–66 (2010).
Gao, P. et al. Deregulation of microRNA expression occurs early and accumulates in early stages of HBV-associated multistep hepatocarcinogenesis . J. Hepatol. 54, 1177–1184 (2011).
Wong, C. M. et al. Sequential alterations of microRNA expression in hepatocellular carcinoma development and venous metastasis . Hepatology 55, 1453–1461 (2012).
Wong, C. M., Kai, A. K., Tsang, F. H. & Ng, I. O. Regulation of hepatocarcinogenesis by microRNAs . Front. Biosci. 5, 49–60 (2013).
Giordano, S. & Columbano, A. MicroRNAs: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma? Hepatology 57, 840–847 (2013).
Borel, F., Konstantinova, P. & Jansen, P. L. Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma . J. Hepatol. 56, 1371–1383 (2012).
Mizuguchi, Y., Takizawa, T., Yoshida, H. & Uchida, E. Dysregulated miRNA in progression of hepatocellular carcinoma: A systematic review . Hepatol. Res. 46, 391–406 (2016).
Wang, X. W., Heegaard, N. H. & Orum, H. MicroRNAs in liver disease . Gastroenterology 142, 1431–1443 (2012).
Williams, G. T. & Farzaneh, F. Are snoRNAs and snoRNA host genes new players in cancer? Nat. Rev. Cancer 12, 84–88 (2012).
Xu, G. et al. Small nucleolar RNA 113–111 suppresses tumorigenesis in hepatocellular carcinoma . Mol. Cancer 13, 216 (2014).
Fang, X. et al. SNORD126 promotes HCC and CRC cell growth by activating the PI3K-AKT pathway through FGFR2 . J. Mol. Cell Biol. 9, 243–255 (2017).
Siomi, M. C., Sato, K., Pezic, D. & Aravin, A. A. PIWI-interacting small RNAs: the vanguard of genome defence . Nat. Rev. Mol. Cell Biol. 12, 246–258 (2011).
Rizzo, F. et al. Specific patterns of PIWI-interacting small noncoding RNA expression in dysplastic liver nodules and hepatocellular carcinoma . Oncotarget 7, 54650–54661 (2016).
Law, P. T. et al. Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma . J. Hepatol. 58, 1165–1173 (2013).
Quinn, J. J. & Chang, H. Y. Unique features of long non-coding RNA biogenesis and function . Nat. Rev. Genet. 17, 47–62 (2016).
Ward, M., McEwan, C., Mills, J. D. & Janitz, M. Conservation and tissue-specific transcription patterns of long noncoding RNAs . J. Hum. Transcr 1, 2–9 (2015).
Ma, L., Bajic, V. B. & Zhang, Z. On the classification of long non-coding RNAs . RNA Biol. 10, 925–933 (2013).
Tsang, F. H. et al. Long non-coding RNA HOTTIP is frequently up-regulated in hepatocellular carcinoma and is targeted by tumour suppressive miR-125b . Liver Int. 35, 1597–1606 (2015).
Yang, Y. et al. Recurrently deregulated lncRNAs in hepatocellular carcinoma . Nat. Commun. 8, 14421 (2017).
Wang, Y. et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling . Cell Stem Cell 16, 413–425 (2015).
Zhu, P. et al. LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells . Nat. Commun. 7, 13608 (2016).
Zhu, P. et al. lnc-β-Catm elicits EZH2-dependent beta-catenin stabilization and sustains liver CSC self-renewal . Nat. Struct. Mol. Biol. 23, 631–639 (2016).
Panzitt, K. et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA . Gastroenterology 132, 330–342 (2007).
Lu, Z. et al. Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1) . Oncotarget 7, 241–254 (2016).
Li, S. P. et al. LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway . Oncotarget 7, 42431–42446 (2016).
Cui, M. et al. Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway . Cancer Res. 75, 846–857 (2015).
Gupta, R. A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis . Nature 464, 1071–1076 (2010).
Kogo, R. et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers . Cancer Res. 71, 6320–6326 (2011).
Yang, Z. et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation . Ann. Surg. Oncol. 18, 1243–1250 (2011).
Rinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs . Cell 129, 1311–1323 (2007).
Fu, W. M. et al. Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling . J. Hepatol. 63, 886–895 (2015).
Wang, K. C. et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression . Nature 472, 120–124 (2011).
Quagliata, L. et al. Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients . Hepatology 59, 911–923 (2014).
Li, T. et al. Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma . Oncogene 35, 1575–1584 (2016).
Zhu, X. T., Yuan, J. H., Zhu, T. T., Li, Y. Y. & Cheng, X. Y. Long noncoding RNA glypican 3 (GPC3) antisense transcript 1 promotes hepatocellular carcinoma progression via epigenetically activating GPC3 . FEBS J. 283, 3739–3754 (2016).
Yuan, S. X. et al. Antisense long non-coding RNA PCNA-AS1 promotes tumor growth by regulating proliferating cell nuclear antigen in hepatocellular carcinoma . Cancer Lett. 349, 87–94 (2014).
Liu, Z. et al. Long non-coding RNA HNF1A-AS1 functioned as an oncogene and autophagy promoter in hepatocellular carcinoma through sponging hsa-miR-30b-5p . Biochem. Biophys. Res. Commun. 473, 1268–1275 (2016).
Li, T. et al. Amplification of long noncoding RNA ZFAS1 promotes metastasis in hepatocellular carcinoma . Cancer Res. 75, 3181–3191 (2015).
Salzman, J. Circular RNA expression: its potential regulation and function . Trends Genet. 32, 309–316 (2016).
Jeck, W. R. et al. Circular RNAs are abundant, conserved, and associated with ALU repeats . RNA 19, 141–157 (2013).
Salzman, J., Gawad, C., Wang, P. L., Lacayo, N. & Brown, P. O. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types . PLoS ONE 7, e30733 (2012).
Yu, L. et al. The Circular RNA Cdr1as Act as an oncogene in hepatocellular carcinoma through targeting miR-7 expression . PLoS ONE 11, e0158347 (2016).
Enuka, Y. et al. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor . Nucleic Acids Res. 44, 1370–1383 (2016).
Peng, H. et al. Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma . Oncotarget 6, 5666–5677 (2015).
Chen, C. L. et al. Suppression of hepatocellular carcinoma by baculovirus-mediated expression of long non-coding RNA PTENP1 and microRNA regulation . Biomaterials 44, 71–81 (2015).
Wang, L. et al. Pseudogene OCT4-pg4 functions as a natural micro RNA sponge to regulate OCT4 expression by competing for miR-145 in hepatocellular carcinoma . Carcinogenesis 34, 1773–1781 (2013).
Jopling, C. Liver-specific microRNA-122: biogenesis and function . RNA Biol. 9, 137–142 (2012).
Krutzfeldt, J. et al. Silencing of microRNAs in vivo with 'antagomirs' . Nature 438, 685–689 (2005).
Li, C. et al. Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels . Oncotarget 7, 17021–17034 (2016).
Kutay, H. et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas . J. Cell. Biochem. 99, 671–678 (2006).
Coulouarn, C., Factor, V. M., Andersen, J. B., Durkin, M. E. & Thorgeirsson, S. S. Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties . Oncogene 28, 3526–3536 (2009).
Wang, B. et al. Reciprocal regulation of microRNA-122 and c-Myc in hepatocellular cancer: role of E2F1 and transcription factor dimerization partner 2 . Hepatology 59, 555–566 (2014).
Fornari, F. et al. MiR-122/cyclin G1 interaction modulates p53 activity and affects doxorubicin sensitivity of human hepatocarcinoma cells . Cancer Res. 69, 5761–5767 (2009).
Wang, S. C. et al. MicroRNA-122 triggers mesenchymal-epithelial transition and suppresses hepatocellular carcinoma cell motility and invasion by targeting RhoA . PLoS ONE 9, e101330 (2014).
Xu, J. et al. MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/ β-catenin pathway . Liver Int. 32, 752–760 (2012).
Simerzin, A. et al. The liver-specific microRNA-122*, the complementary strand of microRNA-122, acts as a tumor suppressor by modulating the p53/mouse double minute 2 homolog circuitry . Hepatology 64, 1623–1636 (2016).
Hou, J. et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma . Cancer Cell 19, 232–243 (2011).
Fornari, F. et al. MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells . Cancer Res. 70, 5184–5193 (2010).
Guo, W. et al. MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer . Hepatology 62, 1132–1144 (2015).
Zhang, L. F. et al. Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma . EMBO J. 34, 2671–2685 (2015).
Fornari, F. et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma . Oncogene 27, 5651–5661 (2008).
Gramantieri, L. et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality . Clin. Cancer Res. 15, 5073–5081 (2009).
Li, J., Wang, Y., Yu, W., Chen, J. & Luo, J. Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance . Biochem. Biophys. Res. Commun. 406, 70–73 (2011).
Garofalo, M. et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation . Cancer Cell 16, 498–509 (2009).
Callegari, E. et al. Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model . Hepatology 56, 1025–1033 (2012).
Fornari, F. et al. In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis . Clin. Cancer Res. 23, 3953–3965 (2017).
Parkin, D. M. The global health burden of infection-associated cancers in the year 2002 . Int. J. Cancer 118, 3030–3044 (2006).
Hessein, M. et al. Hit-and-run mechanism of HBV-mediated progression to hepatocellular carcinoma . Tumori 91, 241–247 (2005).
Chiu, Y. T. et al. Novel pre-mRNA splicing of intronically integrated HBV generates oncogenic chimera in hepatocellular carcinoma . J. Hepatol. 64, 1256–1264 (2016).
Wang, C. et al. Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice . Hepatology 55, 108–120 (2012).
Wu, G. et al. Hepatitis B virus X protein downregulates expression of the miR-16 family in malignant hepatocytes in vitro . Br. J. Cancer 105, 146–153 (2011).
Xu, X. et al. Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis . J. Clin. Invest. 123, 630–645 (2013).
Li, C. H. et al. Hepatitis B virus X protein promotes hepatocellular carcinoma transformation through interleukin-6 activation of microRNA-21 expression . Eur. J. Cancer 50, 2560–2569 (2014).
Huang, J. L. et al. HBx-related long non-coding RNA DBH-AS1 promotes cell proliferation and survival by activating MAPK signaling in hepatocellular carcinoma . Oncotarget 6, 33791–33804 (2015).
Hu, J. J. et al. HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling . Sci. Rep. 6, 23521 (2016).
Du, Y. 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. 287, 26302–26311 (2012).
Huang, J. F. et al. Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin . Hepatology 57, 1882–1892 (2013).
Lau, C. C. et al. Viral-human chimeric transcript predisposes risk to liver cancer development and progression . Cancer Cell 25, 335–349 (2014).
Liang, H. W. et al. Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122 . J. Hepatol. 64, 278–291 (2016).
Ura, S. et al. Differential microRNA expression between hepatitis B and hepatitis C leading disease progression to hepatocellular carcinoma . Hepatology 49, 1098–1112 (2009).
Li, Y., Masaki, T., Yamane, D., McGivern, D. R. & Lemon, S. M. Competing and noncompeting activities of miR-122 and the 5′ exonuclease Xrn1 in regulation of hepatitis C virus replication . Proc. Natl Acad. Sci. USA 110, 1881–1886 (2013).
Jopling, C. L., Yi, M., Lancaster, A. M., Lemon, S. M. & Sarnow, P. Modulation of hepatitis C virus RNA abundance by a liver-specific microRNA . Science 309, 1577–1581 (2005).
Garcia-Sastre, A. & Evans, M. J. miR-122 is more than a shield for the hepatitis C virus genome . Proc. Natl Acad. Sci. USA 110, 1571–1572 (2013).
Machlin, E. S., Sarnow, P. & Sagan, S. M. Masking the 5′ terminal nucleotides of the hepatitis C virus genome by an unconventional microRNA-target RNA complex . Proc. Natl Acad. Sci. USA 108, 3193–3198 (2011).
Luna, J. M. et al. Hepatitis C virus RNA functionally sequesters miR-122 . Cell 160, 1099–1110 (2015).
Murakami, Y., Aly, H. H., Tajima, A., Inoue, I. & Shimotohno, K. Regulation of the hepatitis C virus genome replication by miR-199a . J. Hepatol. 50, 453–460 (2009).
Pedersen, I. M. et al. Interferon modulation of cellular microRNAs as an antiviral mechanism . Nature 449, 919–922 (2007).
Zhang, Y. et al. Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling . Hepatology 56, 1631–1640 (2012).
Zhang, H. et al. Long non-coding RNA expression profiles of hepatitis C virus-related dysplasia and hepatocellular carcinoma . Oncotarget 6, 43770–43778 (2015).
Wree, A., Broderick, L., Canbay, A., Hoffman, H. M. & Feldstein, A. E. From NAFLD to NASH to cirrhosis-new insights into disease mechanisms . Nat. Rev. Gastroenterol. Hepatol. 10, 627–636 (2013).
Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer . Nat. Rev. Gastroenterol. Hepatol. 10, 656–665 (2013).
Cheung, O. et al. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression . Hepatology 48, 1810–1820 (2008).
Pirola, C. J. et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis . Gut 64, 800–812 (2015).
Xu, Y. et al. A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism . Nat. Commun. 6, 7466 (2015).
Hanin, G. et al. miRNA-132 induces hepatic steatosis and hyperlipidaemia by synergistic multitarget suppression . Gut http://dx.doi.org/10.1136/gutjnl-2016-312869 (2017).
Li, P. et al. A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice . Cell Metab. 21, 455–467 (2015).
Chen, G. et al. LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL) . Sci. Rep. 6, 35531 (2016).
Atanasovska, B. et al. A liver-specific long non-coding RNA with a role in cell viability is elevated in human non-alcoholic steatohepatitis . Hepatology 66, 794–808 (2017).
Zheng, F. et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2 . Gut 61, 278–289 (2012).
Wong, C. C. et al. The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2 . Gastroenterology 140, 322–331 (2011).
Ding, J. et al. Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA . Nat. Cell Biol. 12, 390–399 (2010).
Wong, C. M. et al. MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis . Oncotarget 6, 13658–13670 (2015).
Lin, Y. H. et al. Thyroid hormone receptor represses miR-17 expression to enhance tumor metastasis in human hepatoma cells . Oncogene 32, 4509–4518 (2013).
Fang, J. H. et al. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression . Hepatology 54, 1729–1740 (2011).
Brockhausen, J. et al. miR-181a mediates TGF-beta-induced hepatocyte EMT and is dysregulated in cirrhosis and hepatocellular cancer . Liver Int. 35, 240–253 (2015).
Xia, H., Ooi, L. L. & Hui, K. M. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer . Hepatology 58, 629–641 (2013).
Zhang, J. P. et al. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling . Oncogene 33, 4069–4076 (2014).
Tao, Z. H. et al. miR-612 suppresses the invasive-metastatic cascade in hepatocellular carcinoma . J. Exp. Med. 210, 789–803 (2013).
Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells . EMBO Rep. 9, 582–589 (2008).
Park, S. M., Gaur, A. B., Lengyel, E. & Peter, M. E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2 . Genes Dev. 22, 894–907 (2008).
Yang, P. et al. TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma . Cancer Cell 22, 291–303 (2012).
Zhou, S. L. et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis . Hepatology 63, 1560–1575 (2016).
Yuan, J. H. et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma . Cancer Cell 25, 666–681 (2014).
Sui, C. J. et al. Long noncoding RNA GIHCG promotes hepatocellular carcinoma progression through epigenetically regulating miR-200b/a/429 . J. Mol. Med. 94, 1281–1296 (2016).
Zhang, L. et al. Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma . Carcinogenesis 34, 577–586 (2013).
Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells . Nature 414, 105–111 (2001).
Ma, S. et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells . Gastroenterology 132, 2542–2556 (2007).
Ma, S. et al. miR-130b Promotes CD133+ liver tumor-initiating cell growth and self-renewal via tumor protein 53-induced nuclear protein 1 . Cell Stem Cell 7, 694–707 (2010).
Ji, J. et al. Identification of microRNAs specific for epithelial cell adhesion molecule-positive tumor cells in hepatocellular carcinoma . Hepatology 62, 829–840 (2015).
Li, L. et al. Epigenetic modification of MiR-429 promotes liver tumour-initiating cell properties by targeting Rb binding protein 4 . Gut 64, 156–167 (2015).
Wang, X. et al. Long non-coding RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis . J. Hepatol. 64, 1283–1294 (2016).
Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control . Nat. Rev. Genet. 17, 487–500 (2016).
Morris, K. V. & Mattick, J. S. The rise of regulatory RNA . Nat. Rev. Genet. 15, 423–437 (2014).
Gailhouste, L. et al. miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells . Hepatology 58, 1153–1165 (2013).
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 52, 60–70 (2010).
Chuang, K. H. et al. MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors . Hepatology 62, 466–480 (2015).
Wong, C. M. et al. Up-regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis . Hepatology 63, 474–487 (2016).
Fan, D. N. et al. Histone lysine methyltransferase, suppressor of variegation 3–9 homolog 1, promotes hepatocellular carcinoma progression and is negatively regulated by microRNA-125b . Hepatology 57, 637–647 (2013).
Datta, J. et al. Methylation mediated silencing of MicroRNA-1 gene and its role in hepatocellular carcinogenesis . Cancer Res. 68, 5049–5058 (2008).
Au, S. L. et al. Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis . Hepatology 56, 622–631 (2012).
Huang, M. D. et al. Long non-coding RNA ANRIL is upregulated in hepatocellular carcinoma and regulates cell apoptosis by epigenetic silencing of KLF2 . J. Hematol. Oncol. 8, 50 (2015).
Yang, F. et al. Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans . Hepatology 54, 1679–1689 (2011).
Zhou, M., Zhang, X. Y. & Yu, X. Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma . Biomed. Pharmacother. 85, 348–354 (2017).
Huang, M. D. et al. Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2 . Mol. Cancer 14, 165 (2015).
Li, L. M. et al. Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma . Cancer Res. 70, 9798–9807 (2010).
Zhou, J. et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma . J. Clin. Oncol. 29, 4781–4788 (2011).
Wang, C. et al. Prospective evidence of a circulating microRNA signature as a non-invasive marker of hepatocellular carcinoma in HBV patients . Oncotarget http://dx.doi.org/10.18632/oncotarget.9429 (2016).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02448056 (2015).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02928627 (2017).
Xie, H., Ma, H. & Zhou, D. Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma . Biomed. Res. Int. 2013, 136106 (2013).
Kamel, M. M. et al. Investigation of long noncoding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinoma . Transl Res. 168, 134–145 (2016).
Tang, J. et al. Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in hepatocellular carcinoma . Oncotarget 6, 4505–4515 (2015).
Yang, N. et al. The role of extracellular vesicles in mediating progression, metastasis and potential treatment of hepatocellular carcinoma . Oncotarget 8, 3683–3695 (2017).
Sehgal, A., Vaishnaw, A. & Fitzgerald, K. Liver as a target for oligonucleotide therapeutics . J. Hepatol. 59, 1354–1359 (2013).
Hutvagner, G., Simard, M. J., Mello, C. C. & Zamore, P. D. Sequence-specific inhibition of small RNA function . PLoS Biol. 2, E98 (2004).
Elmen, J. et al. LNA-mediated microRNA silencing in non-human primates . Nature 452, 896–899 (2008).
Park, J. K. et al. miR-221 silencing blocks hepatocellular carcinoma and promotes survival . Cancer Res. 71, 7608–7616 (2011).
Janssen, H. L. et al. Treatment of HCV infection by targeting microRNA . N. Engl. J. Med. 368, 1685–1694 (2013).
Kota, J. et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model . Cell 137, 1005–1017 (2009).
Zheng, F. et al. Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets . PLoS Genet. 11, e1004873 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01829971 (2016).
Beg, M. S. et al. in AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics abstr. C43 (Boston, 2015).
Tang, S. et al. An artificial lncRNA targeting multiple miRNAs overcomes sorafenib resistance in hepatocellular carcinoma cells . Oncotarget 7, 73257–73269 (2016).
Gutschner, T. et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells . Cancer Res. 73, 1180–1189 (2013).
Adams, B. D., Parsons, C., Walker, L., Zhang, W. C. & Slack, F. J. Targeting noncoding RNAs in disease . J. Clin. Invest. 127, 761–771 (2017).
Warner, J. R., Soeiro, R., Birnboim, H. C., Girard, M. & Darnell, J. E. Rapidly labeled HeLa cell nuclear RNA. I. Identif. Zone Sediment. Heterogene. Fraction Separate From Ribosomal Precursor RNA . J. Mol. Biol. 19, 349–361 (1966).
Berget, S. M., Moore, C. & Sharp, P. A. Spliced segments at the 5′ terminus of adenovirus 2 late mRNA . Proc. Natl Acad. Sci. USA 74, 3171–3175 (1977).
Kruger, K. et al. Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena . Cell 31, 147–157 (1982).
Maxwell, E. S. & Fournier, M. J. The small nucleolar RNAs . Annu. Rev. Biochem. 64, 897–934 (1995).
Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 . Cell 75, 843–854 (1993).
Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference . Nature 409, 363–366 (2001).
Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi . Science 305, 1437–1441 (2004).
Brannan, C. I., Dees, E. C., Ingram, R. S. & Tilghman, S. M. The product of the H19 gene may function as an RNA . Mol. Cell. Biol. 10, 28–36 (1990).
Brockdorff, N. et al. Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome . Nature 351, 329–331 (1991).
Williams, T. M. et al. The regulation and evolution of a genetic switch controlling sexually dimorphic traits in Drosophila . Cell 134, 610–623 (2008).
Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila . Cell 128, 1089–1103 (2007).
Le Thomas, A. et al. Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state . Genes Dev. 27, 390–399 (2013).
The study was supported by the Hong Kong Research Grants Council Theme-based Research Scheme (T12-704/16R), the Hong Kong Health and Medical Research Fund (03142996 and 04150776), the S.K. Yee Medical Research Foundation (2011), the University Development Fund of The University of Hong Kong and the Hong Kong Innovation and Technology Commission Fund. I.O.-L.N. is the Loke Yew Professor in Pathology.
Department of Pathology, The University of Hong Kong, Block T, Queen Mary Hospital, Pokfulam, Hong Kong.
State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong Jockey Club Building for Interdisciplinary Research, Hong Kong, Pokfulam, Hong Kong.
C.-M.W. and F.H.-C.T. researched data for the article. C.-M.W., F.H.-C.T. and I.O.-L.N. wrote the Review. C.-M.W. and I.O.-L.N. reviewed and edited the article.
Correspondence to Irene Oi-Lin Ng.
(ncRNAs). RNA transcripts that do not code for protein. ncRNAs can be broadly divided into small ncRNAs and long ncRNAs on the basis of an arbitrary cut-off length of 200 nucleotides. Many ncRNAs play regulatory roles in gene expression and other molecular functions.
(3′UTR). The mRNA sequence after the stop codon. It is a regulatory element and is frequently targeted by microRNA to negatively regulate gene expression.
The 5′ sequence of a mature microRNA usually at position 2–8. The seed sequence governs the specificity of microRNA–mRNA interaction via complementary binding.
(LCSCs). A small subset of cancer cells present within a hepatocellular carcinoma (HCC) tumour that possess self-renewal capability and are implicated in HCC tumour initiation, cancer metastasis and drug resistance. They are characterized by specific surface markers, including CD133, CD13, CD24 and epithelial cell adhesion molecule (EPCAM).
(EMT). A cellular process by which cancer cells lose their epithelial cell features and become more mesenchymal. EMT is known to be important for cancer metastasis.
(PRC2). An epigenetic regulator consisting of histone–lysine N-methyltransferase (EZH2) and Polycomb proteins EED and SUZ12. PCR2 is responsible for installing histone 3 lysine 27 trimethylation at a gene promoter to repress the corresponding gene expression.
(ceRNAs). Endogenous transcripts (mRNA or non-coding RNAs) that function as a molecular sponge to regulate the expression of other RNAs through competing for the binding of shared regulatory microRNA(s).
Mechanisms that regulate gene expression after mRNA transcription, usually through controlling RNA stability or protein translation.
(miR*). A minor form of a microRNA (miRNA) duplex generated by the processing of precursor miRNA by the endoribonuclease Dicer. The other strand — guide stand miRNA — is the major form and is functionally active, mature miRNA. Strand selection in miRNA processing is dependent on the thermodynamic feature of the miRNA duplex, and the passenger stand will normally be degraded. Nevertheless, in some cases the passenger strand is also abundantly expressed and might have activity to regulate post-transcriptional gene expression. Guide strand miRNA and passenger strand miRNA have different seed sequences and target different mRNA populations.
A microRNA (miRNA) mimic that is enclosed in liposome (phospholipid) nanoparticle to form a micelle-like structure. The nanoliposome serves as an miRNA carrier to improve the stability in circulation and enhance entry.

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