MicroRNA and liver cancer

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. HCC is characterized by a poor prognosis and an ever increasing number of scientific studies aim to find new diagnostic, prognostic, and therapeutic targets. MicroRNAs (miRNAs), small non-coding RNAs that regulate the gene expression in many processes, have been shown to play a crucial role in regulating hepatocellular carcinoma. miRNAs may act as oncogenic miRNAs and tumor suppressor miRNAs and regulate cancer cell proliferation, invasion, and metastasis by being differently upregulated or downregulated and targeting the genes related with carcinogenesis. miRNAs secreted from cancer cells are found circulating in the blood, presenting an opportunity for their use as disease-related biomarkers. Moreover, extracellular vesicle-derived miRNAs are known to reflect the cell of origin and function and may provide effective biomarkers for predicting diagnosis and prognosis and new therapeutic target in HCC. In this article, we describe the most recent findings regarding the molecular mechanisms and gene regulation of microRNA in HCC, as well as their application in diagnosis/prognosis and treatment.

Keywords

MicroRNA / hepatocellular carcinoma / diagnosis / extracellular vesicles

References

[1] Fitzmaurice C,Abbasi N,Abd-Allah F.Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study..JAMA Oncol2019;5:1749-68 PMCID:PMC6777271

[2] Xia F,Lau WY,Wen XD.Adjuvant sorafenib after heptectomy for barcelona clinic liver cancer-stage C hepatocellular carcinoma patients..World J Gastroenterol2016;22:5384-92 PMCID:PMC4910659

[3] Matsuura K,Ikeo K,Iio E.Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection..Gastroenterology2017;152:1383-94

[4] Cleary SP,Zhao X,Selitsky SR.Identification of driver genes in hepatocellular carcinoma by exome sequencing..Hepatology2013;58:1693-702 PMCID:PMC3830584

[5] Kan Z,Liu X,Barber TD.Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma..Genome Res2013;23:1422-33 PMCID:PMC3759719

[6] Bartel DP.MicroRNAs: genomics, biogenesis, mechanism, and function..Cell2004;116:281-97

[7] Peng Y.The role of MicroRNAs in human cancer..Signal Transduct Target Ther2016;1:15004 PMCID:PMC5661652

[8] Kim VN,Siomi MC.Biogenesis of small RNAs in animals..Nat Rev Mol Cell Biol2009;10:126-39

[9] Cai X,Cullen BR.Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs..RNA2004;10:1957-66 PMCID:PMC1370684

[10] Kosaka N,Yoshioka Y,Matsuki Y.Secretory mechanisms and intercellular transfer of microRNAs in living cells..J Biol Chem2010;285:17442-52 PMCID:PMC2878508

[11] Alberti C.A framework for understanding the roles of miRNAs in animal development..Development2017;144:2548-59

[12] Andrés-León E,Alonso S.Novel miRNA-mRNA interactions conserved in essential cancer pathways..Sci Rep2017;7:46101 PMCID:PMC5384238

[13] Wong CCL,Tung EKK,Lee JMF.The microRNA miR-139 suppresses metastasis and progression of hepatocellular carcinoma by down-regulating Rho-kinase 2..Gastroenterology2011;140:322-31

[14] Gu W,Wang J.miR-139 regulates the proliferation and invasion of hepatocellular carcinoma through the WNT/TCF-4 pathway..Oncol Rep2014;31:397-404

[15] Nagy A,Menyhart O.Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets..Sci Rep2018;8:9227 PMCID:PMC6003936

[16] Li Y,Li W,Tan X.Oncomirs miRNA-221/222 and tumor suppressors miRNA-199a/195 are crucial miRNAs in liver cancer: a systematic analysis..Dig Dis Sci2016;61:2315-27 PMCID:PMC4943968

[17] Mou T,Wei X,Zheng D.Identification and interaction analysis of key genes and microRNAs in hepatocellular carcinoma by bioinformatics analysis..World J Surg Oncol2017;15:63 PMCID:PMC5356276

[18] Shi KQ,Chen XJ,Wang YQ.Hepatocellular carcinoma associated microRNA expression signature: integrated bioinformatics analysis, experimental validation and clinical significance..Oncotarget2015;6:25093-108 PMCID:PMC4694817

[19] Lou W,Ding B,Xu L.Identification of potential miRNA-mRNA regulatory network contributing to pathogenesis of HBV-related HCC..J Transl Med2019;17:7 PMCID:PMC6317219

[20] Wang JL,Kong X,Chen HY.Candidate microRNA biomarkers in human gastric cancer: a systematic review and validation study..PLoS One2013;8:e73683 PMCID:PMC3767766

[21] Moher D,Tetzlaff J,Group P.Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement..PLoS Med2009;6:e1000097 PMCID:PMC2707599

[22] Witjes CDM,Steyerberg EW,de Man RA.Recently introduced biomarkers for screening of hepatocellular carcinoma: a systematic review and meta-analysis..Hepatol Int2013;7:59-64 PMCID:PMC3601272

[23] le Sage C,Egan DA,Mesman E.Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation..EMBO J2007;26:3699-708 PMCID:PMC1949005

[24] Fornari F,Ferracin M,Sabbioni S.MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma..Oncogene2008;27:5651-61

[25] Santhekadur PK,Gredler R,Srivastava J.Multifunction protein staphylococcal nuclease domain containing 1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves nuclear factor kappaB and miR-221..J Biol Chem2012;287:13952-8 PMCID:PMC3340184

[26] Si ML,Wu H,Wu F.miR-21-mediated tumor growth..Oncogene2007;26:2799-803

[27] Landgraf P,Sheridan R,Iovino N.A mammalian microRNA expression atlas based on small RNA library sequencing..Cell2007;129:1401-14 PMCID:PMC2681231

[28] Ying Q,Guo W,Tian Q.Hypoxia-inducible miR-210 augments the metastatic potential of tumor cells by targeting vacuole membrane protein 1 in hepatocellular carcinoma..Hepatology2011;54:2064-75

[29] Huang X,Bennewith KL,Welford SM.Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation..Mol Cell2009;35:856-67 PMCID:PMC2782615

[30] Zhang Z,Dai H,Imakura M.MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT..Cell Cycle2009;8:2756-68

[31] Chen PJ,Liu WH,Huang HC.Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis..Hepatology2012;56:632-43

[32] Lan SH,Zuchini R,Su IJ.Autophagy-preferential degradation of MIR224 participates in hepatocellular carcinoma tumorigenesis..Autophagy2014;10:1687-9 PMCID:PMC4206546

[33] Fornari F,Chieco P,Calin GA.MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells..Cancer Res2010;70:5184-93

[34] Murakami Y,Tajima A,Shimotohno K.Regulation of the hepatitis C virus genome replication by miR-199a..J Hepatol2009;50:453-60

[35] Hou J,Zhou W,Ding G.Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma..Cancer Cell2011;19:232-43

[36] Guo W,Wang Z,Tan N.MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer..Hepatology2015;62:1132-44

[37] Furuta M,Tanimoto K,Arii S.The tumor-suppressive miR-497-195 cluster targets multiple cell-cycle regulators in hepatocellular carcinoma..PloS One2013;8:e60155 PMCID:PMC3609788

[38] Lagos-Quintana M,Yalcin A,Lendeckel W.Identification of tissue-specific microRNAs from mouse..Curr Biol2002;12:735-9

[39] Girard M,Munnich A,Henrion-Caude A.miR-122, a paradigm for the role of microRNAs in the liver..J Hepatol2008;48:648-56

[40] Hou W,Zheng J.MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins..Hepatology2010;51:1494-504 PMCID:PMC2862129

[41] Krützfeldt J,Braich R,Tuschl T.Silencing of microRNAs in vivo with ‘antagomirs’..Nature2005;438:685-9

[42] Esau C,Murray SF,Pandey SK.MiR-122 regulation of lipid metabolism revealed by in vivo antisense targeting..Cell Metab2006;3:87-98

[43] Elmén J,Schütz S,Petri A.LNA-mediated microRNA silencing in non-human primates..Nature2008;452:896-9

[44] Tsai WC,Hsu CS,Chen SJ.MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis..J Clin Invest2012;122:2884-97 PMCID:PMC3408747

[45] Simerzin A,Rivkin M,Zucman-Rossi J.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..Hepatology2016;64:1623-36

[46] Roy S,Seehawer M,Heinzmann F.microRNA 193a-5p regulates levels of nucleolar- and spindle-associated protein 1 to suppress hepatocarcinogenesis..Gastroenterology2018;155:1951-66 PMCID:PMC6279541

[47] Raemaekers T,Beaudouin J,Van Camp M.NuSAP, a novel microtubule-associated protein involved in mitotic spindle organization..J Cell Biol2003;162:1017-29 PMCID:PMC2172854

[48] Wu H,Li X,Zhao L.MicroRNA-206 prevents the pathogenesis of hepatocellular carcinoma via modulating expression of cMet and Cdk6..Hepatology2017;66:1952-67 PMCID:PMC5696004

[49] Nejak-Bowen KN.Beta-catenin signaling, liver regeneration and hepatocellular cancer: sorting the good from the bad..Semin Cancer Biol2011;21:44-58 PMCID:PMC3050081

[50] Zhang JG,Hong DF,Huang D.MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/beta-catenin pathway..Sci Rep2015;5:8087 PMCID:PMC4310092

[51] You Y,Zhou Y,Zhao X.MicroRNA-766-3p Inhibits tumour progression by targeting Wnt3a in hepatocellular carcinoma..Mol Cells2018;41:830-41 PMCID:PMC6182221

[52] Meng F,Wehbe-Janek H,Jacob ST.MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer..Gastroenterology2007;133:647-58 PMCID:PMC4285346

[53] Wu H,Chen X,Song G.MicroRNA-21 is a potential link between non-alcoholic fatty liver disease and hepatocellular carcinoma via modulation of the HBP1-p53-Srebp1c pathway..Gut2016;65:1850-60 PMCID:PMC4882277

[54] Rong M,Dang Y.Increased miR-221 expression in hepatocellular carcinoma tissues and its role in enhancing cell growth and inhibiting apoptosis in vitro..BMC Cancer2013;13:21 PMCID:PMC3551704

[55] Pineau P,McJunkin K,Battiston C.miR-221 overexpression contributes to liver tumorigenesis..Proc Natl Acad Sci U S A2010;107:264-9 PMCID:PMC2806773

[56] Liu Z,Liu B,Xing E.miRNA-222 promotes liver cancer cell proliferation, migration and invasion and inhibits apoptosis by targeting BBC3..Int J Mol Med2018;42:141-8 PMCID:PMC5979783

[57] Ma D,Gao F,Wu D.miR-224 functions as an onco-miRNA in hepatocellular carcinoma cells by activating AKT signaling..Oncol Lett2012;4:483-8 PMCID:PMC3673647

[58] Yu L,Guo X,Zhang P.MicroRNA-224 upregulation and AKT activation synergistically predict poor prognosis in patients with hepatocellular carcinoma..Cancer Epidemiol2014;38:408-13

[59] Wu GG,He WG,Zhang GX.Mir-184 post-transcriptionally regulates SOX7 expression and promotes cell proliferation in human hepatocellular carcinoma..PLoS One2014;9:e88796 PMCID:PMC3928300

[60] Ohta K,Wang J,Iida Y.MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A..Oncotarget2015;6:3211-24 PMCID:PMC4413648

[61] Sun C,Jiang Q.miR-106b targets DAB2 to promote hepatocellular carcinoma cell proliferation and metastasis..Oncol Lett2018;16:3063-9 PMCID:PMC6096264

[62] Giovannini C,Baglioni M,Giannone F.Suppression of p53 by Notch3 is mediated by Cyclin G1 and sustained by MDM2 and miR-221 axis in hepatocellular carcinoma..Oncotarget2014;5:10607-20 PMCID:PMC4279397

[63] Ramassone A,Veronese A.Epigenetics and microRNAs in cancer..Int J Mol Sci2018;19: PMCID:PMC5855681

[64] Nojima M,Tamori A,Shirabe K.Global, cancer-specific microRNA cluster hypomethylation was functionally associated with the development of non-b non-c hepatocellular carcinoma..Mol Cancer2016;15:31 PMCID:PMC4852433

[65] He XX,Liao JZ,Chang Y.The regulation of microRNA expression by DNA methylation in hepatocellular carcinoma..Mol Biosyst2015;11:532-9

[66] Konno M,Asai A,Shimamura T.Distinct methylation levels of mature microRNAs in gastrointestinal cancers..Nat Commun2019;10:3888 PMCID:PMC6715669

[67] Braconi C.MicroRNA expression profiling: a molecular tool for defining the phenotype of hepatocellular tumors..Hepatology2008;47:1807-9

[68] Yi PS.High expression of miR-21 is not a predictor of poor prognosis in all patients with hepatocellular carcinoma..Mol Clin Oncol2018;8:733-9 PMCID:PMC5921297

[69] Zhou Y,Dai B,Shang L.Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts..J Exp Clin Cancer Res2018;37:324 PMCID:PMC6307162

[70] Shih YT,Zhou J,Lee DY.Endothelial progenitors promote hepatocarcinoma intrahepatic metastasis through monocyte chemotactic protein-1 induction of microRNA-21..Gut2015;64:1132-47

[71] Li Q,Chen C,Xiao H.miR-224 promotion of cell migration and invasion by targeting Homeobox D 10 gene in human hepatocellular carcinoma..J Gastroenterol Hepatol2014;29:835-42

[72] Kogure T,Yan IK,Patel T.Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth..Hepatology2011;54:1237-48 PMCID:PMC3310362

[73] Wei JX,Wan YL,Li GL.Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells..Hepatology2015;61:1284-94 PMCID:PMC4511093

[74] Lin XJ,Yang XJ,Yuan YF.Hepatocellular carcinoma cell-secreted Exosomal MicroRNA-210 promotes angiogenesis in vitro and in vivo..Mol Ther Nucleic Acids2018;11:243-52 PMCID:PMC5992447

[75] Fang JH,Shang LR,Lin YF.Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins..Hepatology2018;68:1459-75

[76] Fang T,Lv G,Wang C.Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer..Nat Commun2018;9:191 PMCID:PMC5768693

[77] Greening DW,Xu R,Chen WS.Exosomes and their roles in immune regulation and cancer..Semin Cell Dev Biol2015;40:72-81

[78] Chen L,Goswami S,Ahn YH.Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression..Nat Commun2014;5:5241 PMCID:PMC4212319

[79] Cortez MA,Valdecanas D,Peltier HJ.PDL1 Regulation by p53 via miR-34..J Natl Cancer Inst2015;108: PMCID:PMC4862407

[80] Ye L,Cheng Y,Wang G.Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1(+) regulatory B-cell expansion..J Immunother Cancer2018;6:145 PMCID:PMC6288912

[81] Yin C,Xu D,Zhao X.SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC..Oncoimmunology2019;8:1601479 PMCID:PMC6527304

[82] Liu J,Yu H,He Y.Endoplasmic reticulum stress causes liver cancer cells to release exosomal mir-23a-3p and up-regulate programmed death ligand 1 expression in macrophages..Hepatology2019;70:241-58 PMCID:PMC6597282

[83] Ji J,Li Y,Yin Y.Diagnostic evaluation of des-gamma-carboxy prothrombin versus α-fetoprotein for hepatitis B virus-related hepatocellular carcinoma in China: a large-scale, multicentre study..PLoS One2016;11:e0153227 PMCID:PMC4829182

[84] Lawrie CH,Dunlop HM,Liggins AP.Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma..Br J Haematol2008;141:672-5

[85] Borel F,Jansen PL.Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma..J Hepatol2012;56:1371-83

[86] Zhou J,Gao X,Wang J.Plasma microRNA panel to diagnose hepatitis B virus- related hepatocellular carcinoma..J Clin Oncol2011;29:4781-8

[87] Jin Y,Goh BKP,Cheow PC.Circulating microRNAs as potential diagnostic and prognostic biomarkers in hepatocellular carcinoma..Sci Rep2019;9:10464 PMCID:PMC6639394

[88] Tan Y,Pan T,Chen L.A serum microRNA panel as potential biomarkers for hepatocellular carcinoma related with hepatitis B virus..PLoS One2014;9:e107986 PMCID:PMC4169601

[89] Zhang Y,Qiu Y,Guo P.Serum microRNA panel for early diagnosis of the onset of hepatocellular carcinoma..Medicine (Baltimore)2017;96:e5642 PMCID:PMC5266158

[90] Huang JT,Ma H,Zhang X.Systematic review and meta-analysis: circulating miRNAs for diagnosis of hepatocellular carcinoma..J Cell Physiol2016;231:328-35

[91] Yamamoto Y,Matsuzaki J,Okusaka T.Highly sensitive circulating microRNA panel for accurate detection of hepatocellular carcinoma in patients with liver disease..Hepatol Commun2020;4:284-97 PMCID:PMC6996324

[92] Foye C,David W,Habboush Y.Comparison of miRNA quantitation by Nanostring in serum and plasma samples..PLoS One2017;12:e0189165 PMCID:PMC5718466

[93] Xu Y,Dai C.High serum microRNA-122 level is independently associated with higher overall survival rate in hepatocellular carcinoma patients..Tumour Biol2015;36:4773-6

[94] Kim SS,Cho HJ,Kim JW.Plasma micoRNA-122 as a predictive marker for treatment response following transarterial chemoembolization in patients with hepatocellular carcinoma..J Gastroenterol Hepatol2017;32:199-207

[95] Liu M,Wang L,Zhou C.Association of serum microRNA expression in hepatocellular carcinomas treated with transarterial chemoembolization and patient survival..PloS One2014;9:e109347 PMCID:PMC4183700

[96] Li J,Yu W,Luo J.Expression of serum miR-221 in human hepatocellular carcinoma and its prognostic significance..Biochem Biophys Res Commun2011;406:70-3

[97] Zhang Y,Guo CC,Xie J.Prognostic value of microRNAs in hepatocellular carcinoma: a meta-analysis..Oncotarget2017;8:107237-57 PMCID:PMC5739810

[98] Shruthi K,Anuradha C.Sorafenib response in hepatocellular carcinoma: microRNAs as tuning forks..Hepatol Res2018;48:5-14

[99] Chuma M,Matsuzaki J,Kumada T.Circulating microRNA-1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma..Hepatol Res2019;49:810-22

[100] Cho HJ,Nam JS,Lee JH.Low levels of circulating microRNA-26a/29a as poor prognostic markers in patients with hepatocellular carcinoma who underwent curative treatment..Clin Res Hepatol Gastroenterol2017;41:181-9

[101] Nishida N,Hagiwara S,Sakurai T.MicroRNAs for the prediction of early response to sorafenib treatment in human hepatocellular carcinoma..Liver Cancer2017;6:113-25 PMCID:PMC5340220

[102] Fornari F,Patrizi C,Marinelli S.In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis..Clin Cancer Res2017;23:3953-65

[103] Teufel M,Köchert K,Finn RS.Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma..Gastroenterology2019;156:1731-41

[104] Chen X,Ma L,Yin Y.Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases..Cell Res2008;18:997-1006

[105] Melo SA,Kahlert C,Gammon ST.Glypican-1 identifies cancer exosomes and detects early pancreatic cancer..Nature2015;523:177-82 PMCID:PMC4825698

[106] Pant S,Burczynski ME.The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker opportunities..Biochem Pharmacol2012;83:1484-94 PMCID:PMC7110994

[107] Pan JH,Zhao XX,Li W.Role of exosomes and exosomal microRNAs in hepatocellular carcinoma: Potential in diagnosis and antitumour treatments (Review)..Int J Mol Med2018;41:1809-16 PMCID:PMC5810235

[108] Sohn W,Kang SH.Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma..Exp Mol Med2015;47:e184 PMCID:PMC4650928

[109] Lee YR,Tak WY,Kweon YO.Circulating exosomal non-coding RNAs as prognostic biomarkers in human hepatocellular carcinoma..Int J Cancer2019;144:1444-52

[110] Afonso MB,Simão AL.Circulating microRNAs as potential biomarkers in non-alcoholic fatty liver disease and hepatocellular carcinoma..J Clin Med2016;5:30 PMCID:PMC4810101

[111] Liu W,Liu B.Diagnostic and prognostic values of serum exosomal microRNA-21 in children with hepatoblastoma: a Chinese population-based study..Pediatr Surg Int2016;32:1059-65

[112] Mjelle R,Bacalbasa N,Sorop A.Comprehensive transcriptomic analyses of tissue, serum, and serum exosomes from hepatocellular carcinoma patients..BMC Cancer2019;19:1007 PMCID:PMC6816220

[113] Sugimachi K,Hirata H,Ueda M.Identification of a bona fide microRNA biomarker in serum exosomes that predicts hepatocellular carcinoma recurrence after liver transplantation..Br J Cancer2015;112:532-8 PMCID:PMC4453648

[114] Suehiro T,Kanda Y,Honda T.Serum exosomal microRNA-122 and microRNA-21 as predictive biomarkers in transarterial chemoembolization-treated hepatocellular carcinoma patients..Oncol Lett2018;16:3267-73 PMCID:PMC6096216

[115] Yuan JH,Wang F,Guo YJ.A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma..Cancer Cell2014;25:666-81

[116] Hoshino A,Shen TL,Hashimoto A.Tumour exosome integrins determine organotropic metastasis..Nature2015;527:329-35 PMCID:PMC4788391

[117] Ling H,Calin GA.MicroRNAs and other non-coding RNAs as targets for anticancer drug development..Nat Rev Drug Discov2013;12:847-65 PMCID:PMC4548803

[118] Fu Y,Huang Z.Recent progress in microRNA-based delivery systems for the treatment of human disease..ExRNA2019;1:24

[119] Lindow M.Discovering the first microrna-targeted drug..J Cell Biol2012;199:407-12 PMCID:PMC3483128

[120] Gebert LF,Crivelli SE,Stoffel M.Miravirsen (SPC3649) can inhibit the biogenesis of miR-122..Nucleic Acids Res2014;42:609-21 PMCID:PMC3874169

[121] Jopling C.Liver-specific microRNA-122..RNA Biol2012;9:137-42 PMCID:PMC3346312

[122] Jopling CL,Sarnow P.Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome..Cell Host Microbe2008;4:77-85 PMCID:PMC3519368

[123] Trajkovski M,Soutschek J,Akin A.MicroRNAs 103 and 107 regulate insulin sensitivity..Nature2011;474:649-53

[124] Regulus Therapeutics I. RG-125 (AZD4076), a microRNA therapeutic targeting microRNA 103/107 for the treatment of NASH in patients with type 2 diabetes/Pre-Diabetes, selected as clinical candidate by AstraZeneca. Press release; 2015.

[125] Aravalli RN.Development of microRNA therapeutics for hepatocellular carcinoma..Diagnostics (Basel)2013;3:170-91 PMCID:PMC4665582

[126] Daige CL,Priddy L,Zhao J.Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer..Mol Cancer Ther2014;13:2352-60

[127] Beg MS,Sachdev J,Kang YK.Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors..Invest New Drugs2017;35:180-8 PMCID:PMC5893501

[128] Sato Y,Sakurai Y,Akita H.A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo..J Control Release2012;163:267-76

[129] Yamamoto N,Munakata T,Tateno C.Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments for chronic HBV infection.J Hepatol2016;64:547-55

[130] Santangelo L,Montaldo C,Strippoli R.Functional roles and therapeutic applications of exosomes in hepatocellular carcinoma..Biomed Res Int2017;2017:2931813

[131] Lötvall J,Hochberg F,Di Vizio D.Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles..J Extracell Vesicles2014;3:26913 PMCID:PMC4275645

[132] Gould SJ.As we wait: coping with an imperfect nomenclature for extracellular vesicles..J Extracell Vesicles2013;2: PMCID:PMC3760635

[133] Ingato D,Sim SJ.Good things come in small packages: Overcoming challenges to harness extracellular vesicles for therapeutic delivery..J Control Release2016;241:174-85

[134] Pomatto MAC,D’Antico S,Tetta C.Improved loading of plasma-derived extracellular vesicles to encapsulate antitumor miRNAs..Mol Ther Methods Clin Dev2019;13:133-44 PMCID:PMC6370572

[135] Baldari S,Magenta A,Toietta G.Extracellular vesicles-encapsulated microRNA-125b produced in genetically modified mesenchymal stromal cells inhibits hepatocellular carcinoma cell proliferation..Cells2019;8:1560 PMCID:PMC6952965