Genetic And Epigenetic Regulation Of E-Cadherin Signaling In Human Hepatocellular Carcinoma

References

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6 ):394–424. doi:10.3322/caac.2149230207593
   PubMed Web of Science ®Google Scholar
• Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4 ):529–538. doi:10.1016/j.jhep.2006.05.01316879891
   PubMed Web of Science ®Google Scholar
• van Roy F. Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat Rev Cancer. 2014;14(2 ):121–134. doi:10.1038/nrc364724442140
   PubMed Web of Science ®Google Scholar
• Harrison OJ, Bahna F, Katsamba PS, et al. Two-step adhesive binding by classical cadherins. Nat Struct Mol Biol. 2010;17(3 ):348–357. doi:10.1038/nsmb.178420190754
   PubMed Web of Science ®Google Scholar
• Nardone V, Lucarelli AP, Dalle Vedove A, et al. Crystal structure of human E-Cadherin-EC1EC2 in complex with a peptidomimetic competitive inhibitor of cadherin homophilic interaction. J Med Chem. 2016;59(10 ):5089–5094. doi:10.1021/acs.jmedchem.5b0148727120112
   PubMed Web of Science ®Google Scholar
• Beavon IR. The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer. 2000;36(13Spec No ):1607–1620. doi:10.1016/s0959-8049(00)00158-110959047
   PubMedGoogle Scholar
• van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008;65(23 ):3756–3788. doi:10.1007/s00018-008-8281-118726070
   PubMed Web of Science ®Google Scholar
• Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg. 2000;87(8 ):992–1005. doi:10.1046/j.1365-2168.2000.01513.x10931041
   PubMed Web of Science ®Google Scholar
• Pokutta S, Weis WI. Structure and mechanism of cadherins and catenins in cell-cell contacts. Annu Rev Cell Dev Biol. 2007;23:237–261. doi:10.1146/annurev.cellbio.22.010305.10424117539752
   PubMed Web of Science ®Google Scholar
• Epifano C, Megias D, Perez-Moreno M. p120-catenin differentially regulates cell migration by Rho-dependent intracellular and secreted signals. EMBO Rep. 2014;15(5 ):592–600. doi:10.1002/embr.20133786824639556
   PubMed Web of Science ®Google Scholar
• Anastasiadis PZ, Reynolds AB. Regulation of Rho GTPases by p120-catenin. Curr Opin Cell Biol. 2001;13(5 ):604–610. doi:10.1016/s0955-0674(00)00258-111544030
   PubMed Web of Science ®Google Scholar
• Ascano JJ, Frierson H Jr, Moskaluk CA, et al. Inactivation of the E-cadherin gene in sporadic diffuse-type gastric cancer. Mod Pathol. 2001;14(10 ):942–949. doi:10.1038/modpathol.388041611598162
   PubMed Web of Science ®Google Scholar
• Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392(6674 ):402–405. doi:10.1038/329189537325
   PubMed Web of Science ®Google Scholar
• Horne HN, Oh H, Sherman ME, et al. E-cadherin breast tumor expression, risk factors and survival: pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium. Sci Rep. 2018;8(1 ):6574. doi:10.1038/s41598-018-23733-429700408
   PubMedGoogle Scholar
• Kanai Y, Ushijima S, Hui AM, et al. The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas. Int J Cancer. 1997;71(3 ):355–359. doi:10.1002/(sici)1097-0215(19970502)71:3<355::aid-ijc8>3.0.co;2-x9139867
   PubMed Web of Science ®Google Scholar
• Zhang X, Yang M, Shi H, et al. Reduced E-cadherin facilitates renal cell carcinoma progression by WNT/beta-catenin signaling activation. Oncotarget. 2017;8(12 ):19566–19576. doi:10.18632/oncotarget.1536128223537
   PubMedGoogle Scholar
• Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016;166(1 ):21–45. doi:10.1016/j.cell.2016.06.02827368099
   PubMed Web of Science ®Google Scholar
• Marcucci F, Stassi G, De Maria R. Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov. 2016;15(5 ):311–325. doi:10.1038/nrd.2015.1326822829
   PubMed Web of Science ®Google Scholar
• Mendonsa AM, Na TY, Gumbiner BM. E-cadherin in contact inhibition and cancer. Oncogene. 2018;37(35 ):4769–4780. doi:10.1038/s41388-018-0304-229780167
   PubMed Web of Science ®Google Scholar
• Perrais M, Chen X, Perez-Moreno M, Gumbiner BM. E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. Mol Biol Cell. 2007;18(6 ):2013–2025. doi:10.1091/mbc.e06-04-034817392517
   PubMed Web of Science ®Google Scholar
• Qian X, Karpova T, Sheppard AM, McNally J, Lowy DR. E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. Embo J. 2004;23(8 ):1739–1748. doi:10.1038/sj.emboj.760013615057284
   PubMed Web of Science ®Google Scholar
• Kourtidis A, Lu R, Pence LJ, Anastasiadis PZ. A central role for cadherin signaling in cancer. Exp Cell Res. 2017;358(1 ):78–85. doi:10.1016/j.yexcr.2017.04.00628412244
   PubMed Web of Science ®Google Scholar
• Lecuit T, Yap AS. E-cadherin junctions as active mechanical integrators in tissue dynamics. Nat Cell Biol. 2015;17(5 ):533–539. doi:10.1038/ncb313625925582
   PubMed Web of Science ®Google Scholar
• McCrea PD, Maher MT, Gottardi CJ. Nuclear signaling from cadherin adhesion complexes. Curr Top Dev Biol. 2015;112:129–196.25733140
   PubMed Web of Science ®Google Scholar
• Hu QP, Kuang JY, Yang QK, Bian XW, Yu SC. Beyond a tumor suppressor: soluble E-cadherin promotes the progression of cancer. Int J Cancer. 2016;138(12 ):2804–2812. doi:10.1002/ijc.2998226704932
   PubMed Web of Science ®Google Scholar
• Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 2012;4(5 ):a008052. doi:10.1101/cshperspect.a00805222438566
   PubMed Web of Science ®Google Scholar
• Schneider JA, Logan SK. Revisiting the role of Wnt/beta-catenin signaling in prostate cancer. Mol Cell Endocrinol. 2018;462(Pt A ):3–8. doi:10.1016/j.mce.2017.02.00828189566
   PubMedGoogle Scholar
• Wang Z, Zhang H, Hou J, et al. Clinical implications of beta-catenin protein expression in breast cancer. Int J Clin Exp Pathol. 2015;8(11 ):14989–14994.26823833
   PubMed Web of Science ®Google Scholar
• Rahmani F, Avan A, Hashemy SI, Hassanian SM. Role of Wnt/beta-catenin signaling regulatory microRNAs in the pathogenesis of colorectal cancer. J Cell Physiol. 2018;233(2 ):811–817. doi:10.1002/jcp.2589728266708
   PubMed Web of Science ®Google Scholar
• Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/beta-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol. 2016;22(2 ):823–832. doi:10.3748/wjg.v22.i2.82326811628
   PubMed Web of Science ®Google Scholar
• Shang S, Hua F, Hu ZW. The regulation of beta-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017;8(20 ):33972–33989. doi:10.18632/oncotarget.1568728430641
   PubMedGoogle Scholar
• Jeanes A, Gottardi CJ, Yap AS. Cadherins and cancer: how does cadherin dysfunction promote tumor progression? Oncogene. 2008;27(55 ):6920–6929. doi:10.1038/onc.2008.34319029934
   PubMed Web of Science ®Google Scholar
• van de Wetering M, Barker N, Harkes IC, et al. Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res. 2001;61(1 ):278–284.11196175
   PubMed Web of Science ®Google Scholar
• Yook JI, Li XY, Ota I, et al. A Wnt-Axin2-GSK3beta cascade regulates snail1 activity in breast cancer cells. Nat Cell Biol. 2006;8(12 ):1398–1406. doi:10.1038/ncb150817072303
   PubMed Web of Science ®Google Scholar
• Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann BG, Kemler R. Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev. 1996;59(1 ):3–10. doi:10.1016/0925-4773(96)00597-78892228
   PubMed Web of Science ®Google Scholar
• Nolan T, Hands RE, Bustin SA. Quantification of mRNA using real-time RT-PCR. Nat Protoc. 2006;1(3 ):1559–1582. doi:10.1038/nprot.2006.23617406449
   PubMed Web of Science ®Google Scholar
• Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10(1 ):57–63. doi:10.1038/nrg248419015660
   PubMed Web of Science ®Google Scholar
• Wetmur JG. DNA probes: applications of the principles of nucleic acid hybridization. Crit Rev Biochem Mol Biol. 1991;26(3–4 ):227–259. doi:10.3109/104092391091140691718662
   PubMed Web of Science ®Google Scholar
• Rouck JE, Krapf JE, Roy J, Huff HC, Das A. Recent advances in nanodisc technology for membrane protein studies (2012–2017). FEBS Lett. 2017;591(14 ):2057–2088. doi:10.1002/1873-3468.1270628581067
   PubMed Web of Science ®Google Scholar
• Ben Ismail M, Carreiras F, Agniel R, et al. Application of APTES-Anti-E-cadherin film for early cancer monitoring. Colloids Surf B Biointerfaces. 2016;146:550–557. doi:10.1016/j.colsurfb.2016.06.04827423102
   PubMed Web of Science ®Google Scholar
• Li S, Mao M. Next generation sequencing reveals genetic landscape of hepatocellular carcinomas. Cancer Lett. 2013;340(2 ):247–253. doi:10.1016/j.canlet.2012.09.02723063663
   PubMed Web of Science ®Google Scholar
• Berx G, Staes K, van Hengel J, et al. Cloning and characterization of the human invasion suppressor gene E-cadherin (CDH1). Genomics. 1995;26(2 ):281–289. doi:10.1016/0888-7543(95)80212-57601454
   PubMed Web of Science ®Google Scholar
• Corso G, Intra M, Trentin C, Veronesi P, Galimberti V. CDH1 germline mutations and hereditary lobular breast cancer. Fam Cancer. 2016;15(2 ):215–219. doi:10.1007/s10689-016-9869-526759166
   PubMed Web of Science ®Google Scholar
• Berx G, Becker KF, Hofler H, van Roy F. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat. 1998;12(4 ):226–237. doi:10.1002/(SICI)1098-1004(1998)12:4<226::AID-HUMU2>3.0.CO;2-D9744472
   PubMed Web of Science ®Google Scholar
• Da Silva L, Parry S, Reid L, et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol. 2008;32(5 ):773–783. doi:10.1097/PAS.0b013e318158d6c518379416
   PubMed Web of Science ®Google Scholar
• Melo S, Figueiredo J, Fernandes MS, et al. Predicting the functional impact of CDH1 missense mutations in hereditary diffuse gastric cancer. Int J Mol Sci. 2017;18(12 ):2687. doi:10.3390/ijms18122687
   PubMed Web of Science ®Google Scholar
• Tamura G, Sakata K, Nishizuka S, et al. Inactivation of the E-cadherin gene in primary gastric carcinomas and gastric carcinoma cell lines. Jpn J Cancer Res. 1996;87(11 ):1153–1159. doi:10.1111/j.1349-7006.1996.tb03125.x9045944
   PubMedGoogle Scholar
• Wang G, Huang CH, Zhao Y, et al. Genetic aberration in primary hepatocellular carcinoma: correlation between p53 gene mutation and loss-of-heterozygosity on chromosome 16q21-q23 and 9p21-p23. Cell Res. 2000;10(4 ):311–323. doi:10.1038/sj.cr.729005811191353
   PubMed Web of Science ®Google Scholar
• Slagle BL, Zhou YZ, Birchmeier W, Scorsone KA. Deletion of the E-cadherin gene in hepatitis B virus-positive Chinese hepatocellular carcinomas. Hepatology. 1993;18(4 ):757–762. doi:10.1002/hep.18401804028104855
   PubMed Web of Science ®Google Scholar
• Wei Y, Van Nhieu JT, Prigent S, Srivatanakul P, Tiollais P, Buendia MA. Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic alterations, beta-catenin expression, and clinical features. Hepatology. 2002;36(3 ):692–701. doi:10.1053/jhep.2002.3534212198663
   PubMed Web of Science ®Google Scholar
• Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5 ):401–404. doi:10.1158/2159-8290.CD-12-009522588877
   PubMed Web of Science ®Google Scholar
• Guichard C, Amaddeo G, Imbeaud S, et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6 ):694–698. doi:10.1038/ng.225622561517
   PubMed Web of Science ®Google Scholar
• Pomo JM, Taylor RM, Gullapalli RR. Influence of TP53 and CDH1 genes in hepatocellular cancer spheroid formation and culture: a model system to understand cancer cell growth mechanics. Cancer Cell Int. 2016;16:44. doi:10.1186/s12935-016-0318-127303212
   PubMed Web of Science ®Google Scholar
• Bulzico D, Torres DC, Ferreira GM, et al. A novel TP53 Mutation Associated with TWIST1 and SIP1 expression in an aggressive adrenocortical carcinoma. Endocr Pathol. 2017;28(4 ):326–331. doi:10.1007/s12022-017-9482-728421464
   PubMed Web of Science ®Google Scholar
• Cheng JC, Auersperg N, Leung PC. Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells. Oncogene. 2011;30(37 ):3930–3942. doi:10.1038/onc.2011.11721478913
   PubMed Web of Science ®Google Scholar
• Liu J, Ruan B, You N, et al. Downregulation of miR-200a induces EMT phenotypes and CSC-like signatures through targeting the beta-catenin pathway in hepatic oval cells. PLoS One. 2013;8(11 ):e79409. doi:10.1371/journal.pone.007940924260215
   PubMed Web of Science ®Google Scholar
• Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018. doi:10.1038/nrdp.2016.1827158749
   PubMed Web of Science ®Google Scholar
• Gong Y, Qin Z, Zhou B, Chen H, Shi Z, Zhang J. MicroRNA-200a inhibits transforming growth factor beta1-induced proximal tubular epithelial-mesenchymal transition by targeting beta-catenin. Nephron. 2017;137(3 ):237–249. doi:10.1159/00047916828817830
   PubMed Web of Science ®Google Scholar
• Yang Z, Liu S, Zhu M, et al. PS341 inhibits hepatocellular and colorectal cancer cells through the FOXO3/CTNNB1 signaling pathway. Sci Rep. 2016;6:22090. doi:10.1038/srep2209026915315
   PubMed Web of Science ®Google Scholar
• Zucman-Rossi J, Benhamouche S, Godard C, et al. Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas. Oncogene. 2007;26(5 ):774–780. doi:10.1038/sj.onc.120982416964294
   PubMed Web of Science ®Google Scholar
• Heng HH, Bremer SW, Stevens JB, et al. Chromosomal instability (CIN): what it is and why it is crucial to cancer evolution. Cancer Metastasis Rev. 2013;32(3–4 ):325–340. doi:10.1007/s10555-013-9427-723605440
   PubMed Web of Science ®Google Scholar
• Wilkinson PD, Delgado ER, Alencastro F, et al. The polyploid state restricts hepatocyte proliferation and liver regeneration in mice. Hepatology. 2019;69(3 ):1242–1258. doi:10.1002/hep.3028630244478
   PubMed Web of Science ®Google Scholar
• Rajagopalan H, Lengauer C. Aneuploidy and cancer. Nature. 2004;432(7015 ):338–341. doi:10.1038/nature0309915549096
   PubMed Web of Science ®Google Scholar
• Sheltzer JM, Amon A. The aneuploidy paradox: costs and benefits of an incorrect karyotype. Trends Genet. 2011;27(11 ):446–453. doi:10.1016/j.tig.2011.07.00321872963
   PubMed Web of Science ®Google Scholar
• Gao C, Su Y, Koeman J, et al. Chromosome instability drives phenotypic switching to metastasis. Proc Natl Acad Sci U S A. 2016;113(51 ):14793–14798. doi:10.1073/pnas.161821511327930335
   PubMed Web of Science ®Google Scholar
• Celesti G, Di Caro G, Bianchi P, et al. Presence of Twist1-positive neoplastic cells in the stroma of chromosome-unstable colorectal tumors. Gastroenterology. 2013;145(3 ):647–657 e615. doi:10.1053/j.gastro.2013.05.01123684708
   PubMed Web of Science ®Google Scholar
• Yang MH, Wu MZ, Chiou SH, et al. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol. 2008;10(3 ):295–305. doi:10.1038/ncb169118297062
   PubMed Web of Science ®Google Scholar
• Yang SW, Zhang ZG, Hao YX, et al. HIF-1alpha induces the epithelial-mesenchymal transition in gastric cancer stem cells through the snail pathway. Oncotarget. 2017;8(6 ):9535–9545. doi:10.18632/oncotarget.1448428076840
   PubMedGoogle Scholar
• Risolino M, Mandia N, Iavarone F, et al. Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-beta-SMAD3 pathway in non-small cell lung adenocarcinoma. Proc Natl Acad Sci U S A. 2014;111(36 ):E3775–E3784. doi:10.1073/pnas.140707411125157139
   PubMed Web of Science ®Google Scholar
• Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19(2 ):156–172. doi:10.1038/cr.2009.519153598
   PubMed Web of Science ®Google Scholar
• Liu YN, Lee WW, Wang CY, Chao TH, Chen Y, Chen JH. Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene. 2005;24(56 ):8277–8290. doi:10.1038/sj.onc.120899116116478
   PubMed Web of Science ®Google Scholar
• Chaudhary J, Skinner MK. Basic helix-loop-helix proteins can act at the E-box within the serum response element of the c-fos promoter to influence hormone-induced promoter activation in sertoli cells. Mol Endocrinol. 1999;13(5 ):774–786. doi:10.1210/mend.13.5.027110319327
   PubMedGoogle Scholar
• Behrens J, Lowrick O, Klein-Hitpass L, Birchmeier W. The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. Proc Natl Acad Sci U S A. 1991;88(24 ):11495–11499. doi:10.1073/pnas.88.24.114951763063
   PubMed Web of Science ®Google Scholar
• Paznekas WA, Okajima K, Schertzer M, Wood S, Jabs EW. Genomic organization, expression, and chromosome location of the human SNAIL gene (SNAI1) and a related processed pseudogene (SNAI1P). Genomics. 1999;62(1 ):42–49. doi:10.1006/geno.1999.601010585766
   PubMed Web of Science ®Google Scholar
• Lin Y, Dong C, Zhou BP. Epigenetic regulation of EMT: the snail story. Curr Pharm Des. 2014;20(11 ):1698–1705. doi:10.2174/1381612811319999051223888971
   PubMed Web of Science ®Google Scholar
• Tong ZT, Cai MY, Wang XG, et al. EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and snail to inhibit E-cadherin. Oncogene. 2012;31(5 ):583–594. doi:10.1038/onc.2011.25421685935
   PubMed Web of Science ®Google Scholar
• Molina-Ortiz P, Villarejo A, MacPherson M, et al. Characterization of the SNAG and SLUG domains of Snail2 in the repression of E-cadherin and EMT induction: modulation by serine 4 phosphorylation. PLoS One. 2012;7(5 ):e36132. doi:10.1371/journal.pone.003613222567133
   PubMed Web of Science ®Google Scholar
• Zhao Z, Rahman MA, Chen ZG, Shin DM. Multiple biological functions of twist1 in various cancers. Oncotarget. 2017;8(12 ):20380–20393. doi:10.18632/oncotarget.1460828099910
   PubMedGoogle Scholar
• Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117(7 ):927–939. doi:10.1016/j.cell.2004.06.00615210113
   PubMed Web of Science ®Google Scholar
• Yang F, Sun L, Li Q, et al. SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities. Embo J. 2012;31(1 ):110–123. doi:10.1038/emboj.2011.36421983900
   PubMed Web of Science ®Google Scholar
• Lander R, Nasr T, Ochoa SD, Nordin K, Prasad MS, Labonne C. Interactions between twist and other core epithelial-mesenchymal transition factors are controlled by GSK3-mediated phosphorylation. Nat Commun. 2013;4:1542. doi:10.1038/ncomms254323443570
   PubMed Web of Science ®Google Scholar
• Forghanifard MM, Ardalan Khales S, Farshchian M, Rad A, Homayouni-Tabrizi M, Abbaszadegan MR. Negative regulatory role of TWIST1 on SNAIL gene expression. Pathol Oncol Res. 2017;23(1 ):85–90. doi:10.1007/s12253-016-0093-227438288
   PubMed Web of Science ®Google Scholar
• Sanchez-Tillo E, Lazaro A, Torrent R, et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene. 2010;29(24 ):3490–3500. doi:10.1038/onc.2010.10220418909
   PubMed Web of Science ®Google Scholar
• Comijn J, Berx G, Vermassen P, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001;7(6 ):1267–1278. doi:10.1016/s1097-2765(01)00260-x11430829
   PubMed Web of Science ®Google Scholar
• Bassez G, Camand OJ, Cacheux V, et al. Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the “Mowat-Wilson” syndrome. Neurobiol Dis. 2004;15(2 ):240–250. doi:10.1016/j.nbd.2003.10.00415006694
   PubMed Web of Science ®Google Scholar
• He Y, Northey JJ, Pelletier A, et al. The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer. Oncogene. 2017;36(24 ):3490–3503. doi:10.1038/onc.2016.49228135249
   PubMed Web of Science ®Google Scholar
• Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev. 2009;23(7 ):781–783. doi:10.1101/gad.178760919339683
   PubMed Web of Science ®Google Scholar
• Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150(1 ):12–27. doi:10.1016/j.cell.2012.06.01322770212
   PubMed Web of Science ®Google Scholar
• Matsumura T, Makino R, Mitamura K. Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. Clin Cancer Res. 2001;7(3 ):594–599.11297254
   PubMed Web of Science ®Google Scholar
• Zlotorynski E. Epigenetics: DNA methylation prevents intragenic transcription. Nat Rev Mol Cell Biol. 2017;18(4 ):212–213. doi:10.1038/nrm.2017.18
   Web of Science ®Google Scholar
• Traube FR, Carell T. The chemistries and consequences of DNA and RNA methylation and demethylation. RNA Biol. 2017;14(9 ):1099–1107. doi:10.1080/15476286.2017.131824128440690
   PubMed Web of Science ®Google Scholar
• Chiba T, Yokosuka O, Fukai K, et al. Identification and investigation of methylated genes in hepatoma. Eur J Cancer. 2005;41(8 ):1185–1194. doi:10.1016/j.ejca.2005.02.01415911243
   PubMed Web of Science ®Google Scholar
• Yang B, Guo M, Herman JG, Clark DP. Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. Am J Pathol. 2003;163(3 ):1101–1107. doi:10.1016/S0002-9440(10)63469-412937151
   PubMed Web of Science ®Google Scholar
• Lee S, Lee HJ, Kim JH, Lee HS, Jang JJ, Kang GH. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163(4 ):1371–1378. doi:10.1016/S0002-9440(10)63495-514507645
   PubMed Web of Science ®Google Scholar
• Arzumanyan A, Friedman T, Kotei E, Ng IO, Lian Z, Feitelson MA. Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer. Oncogene. 2012;31(5 ):563–572. doi:10.1038/onc.2011.25521706058
   PubMed Web of Science ®Google Scholar
• Liu J, Lian Z, Han S, et al. Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma. Oncogene. 2006;25(7 ):1008–1017. doi:10.1038/sj.onc.120913816247464
   PubMed Web of Science ®Google Scholar
• Qiu X, Qiao F, Su X, Zhao Z, Fan H. Epigenetic activation of E-cadherin is a candidate therapeutic target in human hepatocellular carcinoma. Exp Ther Med. 2010;1(3 ):519–523. doi:10.3892/etm_0000008222993570
   PubMed Web of Science ®Google Scholar
• Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci U S A. 1995;92(16 ):7416–7419. doi:10.1073/pnas.92.16.74167543680
   PubMed Web of Science ®Google Scholar
• Tanaka M, Katayama F, Kato H, et al. Hepatitis B and C virus infection and hepatocellular carcinoma in China: a review of epidemiology and control measures. J Epidemiol. 2011;21(6 ):401–416. doi:10.2188/jea.JE2010019022041528
   PubMed Web of Science ®Google Scholar
• Lee JO, Kwun HJ, Jung JK, Choi KH, Min DS, Jang KL. Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyltransferase 1. Oncogene. 2005;24(44 ):6617–6625. doi:10.1038/sj.onc.120882716007161
   PubMed Web of Science ®Google Scholar
• Arora P, Kim EO, Jung JK, Jang KL. Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. Cancer Lett. 2008;261(2 ):244–252. doi:10.1016/j.canlet.2007.11.03318164808
   PubMed Web of Science ®Google Scholar
• Hermann A, Goyal R, Jeltsch A. The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem. 2004;279(46 ):48350–48359. doi:10.1074/jbc.M40342720015339928
   PubMed Web of Science ®Google Scholar
• Lim SO, Gu JM, Kim MS, et al. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology. 2008;135(6 ):2128–2140, 2140 e2121–2140 2128. doi:10.1053/j.gastro.2008.07.027
   Web of Science ®Google Scholar
• Cheng X. Structural and functional coordination of DNA and histone methylation. Cold Spring Harb Perspect Biol. 2014;6(8 ):a018747. doi:10.1101/cshperspect.a01874725085914
   PubMed Web of Science ®Google Scholar
• Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10 ):1057–1068. doi:10.1038/nbt.168520944598
   PubMed Web of Science ®Google Scholar
• Bannister AJ, Schneider R, Kouzarides T. Histone methylation: dynamic or static? Cell. 2002;109(7 ):801–806. doi:10.1016/s0092-8674(02)00798-512110177
   PubMed Web of Science ®Google Scholar
• Song Y, Wu F, Wu J. Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives. J Hematol Oncol. 2016;9(1 ):49. doi:10.1186/s13045-016-0279-927316347
   PubMedGoogle Scholar
• Bernstein BE, Kamal M, Lindblad-Toh K, et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell. 2005;120(2 ):169–181. doi:10.1016/j.cell.2005.01.00115680324
   PubMed Web of Science ®Google Scholar
• Dong C, Wu Y, Yao J, et al. G9a interacts with snail and is critical for snail-mediated E-cadherin repression in human breast cancer. J Clin Invest. 2012;122(4 ):1469–1486. doi:10.1172/JCI5734922406531
   PubMed Web of Science ®Google Scholar
• Yokoyama M, Chiba T, Zen Y, et al. Histone lysine methyltransferase G9a is a novel epigenetic target for the treatment of hepatocellular carcinoma. Oncotarget. 2017;8(13 ):21315–21326. doi:10.18632/oncotarget.1552828423509
   PubMedGoogle Scholar
• Ramadoss S, Chen X, Wang CY. Histone demethylase KDM6B promotes epithelial-mesenchymal transition. J Biol Chem. 2012;287(53 ):44508–44517. doi:10.1074/jbc.M112.42490323152497
   PubMed Web of Science ®Google Scholar
• Monga SP. beta-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015;148(7 ):1294–1310. doi:10.1053/j.gastro.2015.02.05625747274
   PubMed Web of Science ®Google Scholar
• Zhang J, Tian XJ, Xing J. Signal transduction pathways of EMT induced by TGF-beta, SHH, and WNT and their crosstalks. J Clin Med. 2016;5(4 ):41. doi:10.3390/jcm5040041
   PubMed Web of Science ®Google Scholar
• Feng B, Zhu Y, Su Z, et al. Basil polysaccharide attenuates hepatocellular carcinoma metastasis in rat by suppressing H3K9me2 histone methylation under hepatic artery ligation-induced hypoxia. Int J Biol Macromol. 2018;107(Pt B ):2171–2179. doi:10.1016/j.ijbiomac.2017.10.08829042275
   PubMedGoogle Scholar
• Tan JZ, Yan Y, Wang XX, Jiang Y, Xu HE. EZH2: biology, disease, and structure-based drug discovery. Acta Pharmacol Sin. 2014;35(2 ):161–174. doi:10.1038/aps.2013.16124362326
   PubMed Web of Science ®Google Scholar
• Cai MY, Hou JH, Rao HL, et al. High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. Mol Med. 2011;17(1–2 ):12–20. doi:10.2119/molmed.2010.0010320844838
   PubMed Web of Science ®Google Scholar
• Battistelli C, Cicchini C, Santangelo L, et al. The snail repressor recruits EZH2 to specific genomic sites through the enrollment of the lncRNA HOTAIR in epithelial-to-mesenchymal transition. Oncogene. 2017;36(7 ):942–955. doi:10.1038/onc.2016.26027452518
   PubMed Web of Science ®Google Scholar
• Li CP, Cai MY, Jiang LJ, et al. CLDN14 is epigenetically silenced by EZH2-mediated H3K27ME3 and is a novel prognostic biomarker in hepatocellular carcinoma. Carcinogenesis. 2016;37(6 ):557–566. doi:10.1093/carcin/bgw03627207647
   PubMed Web of Science ®Google Scholar
• Verdin E, Ott M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat Rev Mol Cell Biol. 2015;16(4 ):258–264. doi:10.1038/nrm393125549891
   PubMed Web of Science ®Google Scholar
• Lei W, Zhang K, Pan X, et al. Histone deacetylase 1 is required for transforming growth factor-beta1-induced epithelial-mesenchymal transition. Int J Biochem Cell Biol. 2010;42(9 ):1489–1497. doi:10.1016/j.biocel.2010.05.00620580679
   PubMed Web of Science ®Google Scholar
• Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21(1 ):103–107. doi:10.1038/50479916800
   PubMed Web of Science ®Google Scholar
• Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP. DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet. 2000;25(3 ):338–342. doi:10.1038/7712410888886
   PubMed Web of Science ®Google Scholar
• Roche J, Nasarre P, Gemmill R, et al. Global decrease of histone H3K27 acetylation in ZEB1-induced epithelial to mesenchymal transition in lung cancer cells. Cancers (Basel). 2013;5(2 ):334–356. doi:10.3390/cancers502033424216980
   PubMedGoogle Scholar
• Yang G, Zeng X, Wang M, Wu A. The TET2/E-cadherin/beta-catenin regulatory loop confers growth and invasion in hepatocellular carcinoma cells. Exp Cell Res. 2018;363(2 ):218–226. doi:10.1016/j.yexcr.2018.01.01129331390
   PubMed Web of Science ®Google Scholar
• Xu W, Liu H, Liu ZG, et al. Histone deacetylase inhibitors upregulate snail via smad2/3 phosphorylation and stabilization of snail to promote metastasis of hepatoma cells. Cancer Lett. 2018;420:1–13. doi:10.1016/j.canlet.2018.01.06829410023
   PubMed Web of Science ®Google Scholar
• Derynck R, Zhang YE. Smad-dependent and smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958 ):577–584. doi:10.1038/nature0200614534577
   PubMed Web of Science ®Google Scholar
• Chang R, Zhang Y, Zhang P, Zhou Q. Snail acetylation by histone acetyltransferase p300 in lung cancer. Thorac Cancer. 2017;8(3 ):131–137. doi:10.1111/1759-7714.1240828296173
   PubMed Web of Science ®Google Scholar
• Yokomizo C, Yamaguchi K, Itoh Y, et al. High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells. Cancer Lett. 2011;310(2 ):140–147. doi:10.1016/j.canlet.2011.06.03021764211
   PubMed Web of Science ®Google Scholar
• Song Y, Li ZX, Liu X, Wang R, Li LW, Zhang Q. The Wnt/beta-catenin and PI3K/Akt signaling pathways promote EMT in gastric cancer by epigenetic regulation via H3 lysine 27 acetylation. Tumour Biol. 2017;39(7 ):1010428317712617. doi:10.1177/101042831771261728671020
   PubMedGoogle Scholar
• He Y, Meng XM, Huang C, et al. Long noncoding RNAs: novel insights into hepatocelluar carcinoma. Cancer Lett. 2014;344(1 ):20–27. doi:10.1016/j.canlet.2013.10.02124183851
   PubMed Web of Science ®Google Scholar
• Yuan JH, Yang F, Wang F, et al. A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;25(5 ):666–681. doi:10.1016/j.ccr.2014.03.01024768205
   PubMed Web of Science ®Google Scholar
• Zhang J, Han C, Ungerleider N, et al. A transforming growth factor-beta and H19 signaling axis in tumor-initiating hepatocytes that regulates hepatic carcinogenesis. Hepatology. 2018.
   Web of Science ®Google Scholar
• Zhou Y, Fan RG, Qin CL, Jia J, Wu XD, Zha WZ. LncRNA-H19 activates CDC42/PAK1 pathway to promote cell proliferation, migration and invasion by targeting miR-15b in hepatocellular carcinoma. Genomics. 2018. doi:10.1016/j.ygeno.2018.12.009
   Web of Science ®Google Scholar
• Ge XS, Ma HJ, Zheng XH, et al. HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF-1 expression and activates Wnt pathway. Cancer Sci. 2013;104(12 ):1675–1682.24118380
   PubMed Web of Science ®Google Scholar
• Liang WC, Ren JL, Wong CW, et al. LncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/beta-catenin signaling. Oncogene. 2018;37(11 ):1445–1456. doi:10.1038/s41388-017-0041-y29311643
   PubMed Web of Science ®Google Scholar
• Li Y, Guo D, Zhao Y, et al. Long non-coding RNA SNHG5 promotes human hepatocellular carcinoma progression by regulating miR-26a-5p/GSK3beta signal pathway. Cell Death Dis. 2018;9(9 ):888. doi:10.1038/s41419-018-1111-y30166525
   PubMedGoogle Scholar
• Chen W, You J, Zheng Q, Zhu YY. Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/beta-catenin signaling pathways. Cancer Manag Res. 2018;10:1817–1826. doi:10.2147/CMAR.S16491129997441
   PubMed Web of Science ®Google Scholar
• Zhu L, Yang N, Du G, et al. LncRNA CRNDE promotes the epithelial-mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/beta-catenin signaling pathway. J Cell Biochem. 2018.
   Google Scholar
• Li SP, Xu HX, Yu Y, 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. 2016;7(27 ):42431–42446. doi:10.18632/oncotarget.988327285757
   PubMed Web of Science ®Google Scholar
• Yang T, He X, Chen A, Tan K, Du X. LncRNA HOTAIR contributes to the malignancy of hepatocellular carcinoma by enhancing epithelial-mesenchymal transition via sponging miR-23b-3p from ZEB1. Gene. 2018;670:114–122. doi:10.1016/j.gene.2018.05.06129778425
   PubMed Web of Science ®Google Scholar
• Dou C, Sun L, Jin X, et al. Long non-coding RNA CARLo-5 promotes tumor progression in hepatocellular carcinoma via suppressing miR-200b expression. Oncotarget. 2017;8(41 ):70172–70182. doi:10.18632/oncotarget.1959729050269
   PubMedGoogle Scholar
• Lan T, Chang L, Wu L, Yuan Y. Downregulation of ZEB2-AS1 decreased tumor growth and metastasis in hepatocellular carcinoma. Mol Med Rep. 2016;14(5 ):4606–4612. doi:10.3892/mmr.2016.583627748842
   PubMed Web of Science ®Google Scholar
• Caramel J, Ligier M, Puisieux A. Pleiotropic roles for ZEB1 in cancer. Cancer Res. 2018;78(1 ):30–35. doi:10.1158/0008-5472.CAN-17-247629254997
   PubMed Web of Science ®Google Scholar
• Ma M, Xu H, Liu G, et al. MITA1, a novel energy stress-inducible lncRNA, promotes hepatocellular carcinoma metastasis. Hepatology. 2019. doi:10.1002/hep.30602
   Google Scholar
• Cao SW, Huang JL, Chen J, et al. Long non-coding RNA UBE2CP3 promotes tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget. 2017;8(39 ):65370–65385. doi:10.18632/oncotarget.1852429029437
   PubMedGoogle Scholar
• Xiao JN, Yan TH, Yu RM, et al. Long non-coding RNA UCA1 regulates the expression of snail2 by miR-203 to promote hepatocellular carcinoma progression. J Cancer Res Clin Oncol. 2017;143(6 ):981–990. doi:10.1007/s00432-017-2370-128271214
   PubMed Web of Science ®Google Scholar
• Sun J, Wei X, Xu L. Upregulation of lncRNA Sox2ot indicates a poor prognosis for patients with hepatocellular carcinoma and promotes cell invasion. Oncol Lett. 2018;16(1 ):1189–1195. doi:10.3892/ol.2018.872529963193
   PubMed Web of Science ®Google Scholar
• Zhou M, Zhang XY, 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. 2017;85:348–354. doi:10.1016/j.biopha.2016.11.03527899259
   PubMed Web of Science ®Google Scholar
• Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9 ):597–610. doi:10.1038/nrg284320661255
   PubMed Web of Science ®Google Scholar
• Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3 ):203–222. doi:10.1038/nrd.2016.24628209991
   PubMed Web of Science ®Google Scholar
• Roderburg C, Trautwein C. Cell-specific functions of miRNA in the liver. J Hepatol. 2017;66(3 ):655–656. doi:10.1016/j.jhep.2016.09.01527702640
   PubMed Web of Science ®Google Scholar
• Hsu SH, Delgado ER, Otero PA, et al. MicroRNA-122 regulates polyploidization in the murine liver. Hepatology. 2016;64(2 ):599–615. doi:10.1002/hep.2857327016325
   PubMed Web of Science ®Google Scholar
• Jin Y, Wang J, Han J, Luo D, Sun Z. MiR-122 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting snail1 and Snail2 and suppressing WNT/beta-cadherin signaling pathway. Exp Cell Res. 2017;360(2 ):210–217. doi:10.1016/j.yexcr.2017.09.01028890291
   PubMed Web of Science ®Google Scholar
• Wang N, Wang Q, Shen D, Sun X, Cao X, Wu D. Downregulation of microRNA-122 promotes proliferation, migration, and invasion of human hepatocellular carcinoma cells by activating epithelial-mesenchymal transition. Onco Targets Ther. 2016;9:2035–2047. doi:10.2147/OTT.S9237827103830
   PubMed Web of Science ®Google Scholar
• Liang HW, Wang N, Wang Y, et al. Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122. J Hepatol. 2016;64(2 ):278–291. doi:10.1016/j.jhep.2015.09.01326409216
   PubMed Web of Science ®Google Scholar
• Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22(7 ):894–907. doi:10.1101/gad.164060818381893
   PubMed Web of Science ®Google Scholar
• Ding W, Dang H, You H, et al. miR-200b restoration and DNA methyltransferase inhibitor block lung metastasis of mesenchymal-phenotype hepatocellular carcinoma. Oncogenesis. 2012;1:e15. doi:10.1038/oncsis.2012.1523552699
   PubMed Web of Science ®Google Scholar
• Wu G, Zheng K, Xia S, et al. MicroRNA-655-3p functions as a tumor suppressor by regulating ADAM10 and beta-catenin pathway in hepatocellular carcinoma. J Exp Clin Cancer Res. 2016;35(1 ):89. doi:10.1186/s13046-016-0444-627259866
   PubMedGoogle Scholar
• Li H, Wang H, Ren Z. MicroRNA-214-5p inhibits the invasion and migration of hepatocellular carcinoma cells by targeting wiskott-aldrich syndrome like. Cell Physiol Biochem. 2018;46(2 ):757–764. doi:10.1159/00048873429621773
   PubMedGoogle Scholar
• Huang J, Wang Y, Guo Y, Sun S. Down-regulated microRNA-152 induces aberrant DNA methylation in hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology. 2010;52(1 ):60–70. doi:10.1002/hep.2366020578129
   PubMed Web of Science ®Google Scholar
• Wu LQ, Lu Y, Lu HJ, Lv ZH. Can E-cadherin and CD34 be used as indicators of prognosis for hepatocellular carcinoma patients? Clin Chem Lab Med. 2008;46(8 ):1122–1126. doi:10.1515/CCLM.2008.23118724809
   PubMed Web of Science ®Google Scholar
• Chen J, Zhao J, Ma R, Lin H, Liang X, Cai X. Prognostic significance of E-cadherin expression in hepatocellular carcinoma: a meta-analysis. PLoS One. 2014;9(8 ):e103952. doi:10.1371/journal.pone.010395225093414
   PubMed Web of Science ®Google Scholar
• Lachenmayer A, Toffanin S, Cabellos L, et al. Combination therapy for hepatocellular carcinoma: additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib. J Hepatol. 2012;56(6 ):1343–1350. doi:10.1016/j.jhep.2012.01.00922322234
   PubMed Web of Science ®Google Scholar
• Catela Ivkovic T, Voss G, Cornella H, Ceder Y. microRNAs as cancer therapeutics: a step closer to clinical application. Cancer Lett. 2017;407:113–122. doi:10.1016/j.canlet.2017.04.00728412239
   PubMed Web of Science ®Google Scholar
• Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet. 2014;15(8 ):541–555. doi:10.1038/nrg376325022906
   PubMed Web of Science ®Google Scholar
• Zhang J, Han C, Ungerleider N, et al. A transforming growth factor-beta and H19 signaling axis in tumor-initiating hepatocytes that regulates hepatic carcinogenesis. Hepatology. 2019;69(4 ):1549–1563. doi:10.1002/hep.3015330014520
   PubMed Web of Science ®Google Scholar
• Ye Y, Xu Y, Lai Y, et al. Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization. J Cell Biochem. 2018;119(3 ):2951–2963. doi:10.1002/jcb.2650929131381
   PubMed Web of Science ®Google Scholar
• Ding G, Peng Z, Shang J, Kang Y, Ning H, Mao C. LincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through miR-9/E-cadherin cascade signaling pathway molecular mechanism. Onco Targets Ther. 2017;10:3241–3247. doi:10.2147/OTT.S13491028721075
   PubMed Web of Science ®Google Scholar
• Liu J, Lu C, Xiao M, Jiang F, Qu L, Ni R. Long non-coding RNA SNHG20 predicts a poor prognosis for HCC and promotes cell invasion by regulating the epithelial-to-mesenchymal transition. Biomed Pharmacother. 2017;89:857–863. doi:10.1016/j.biopha.2017.01.01128282787
   PubMed Web of Science ®Google Scholar
• Heller G, Altenberger C, Steiner I, et al. DNA methylation of microRNA-coding genes in non-small-cell lung cancer patients. J Pathol. 2018;245(4 ):387–398. doi:10.1002/path.507929570800
   PubMed Web of Science ®Google Scholar
• Gou X, Zhao X, Wang Z. Long noncoding RNA PVT1 promotes hepatocellular carcinoma progression through regulating miR-214. Cancer Biomark. 2017;20(4 ):511–519. doi:10.3233/CBM-17033128800314
   PubMed Web of Science ®Google Scholar
• Deng X, Zhao XF, Liang XQ, Chen R, Pan YF, Liang J. Linc00152 promotes cancer progression in hepatitis B virus-associated hepatocellular carcinoma. Biomed Pharmacother. 2017;90:100–108. doi:10.1016/j.biopha.2017.03.03128343069
   PubMed Web of Science ®Google Scholar
• Zhou T, Gao Y. Increased expression of LncRNA BANCR and its prognostic significance in human hepatocellular carcinoma. World J Surg Oncol. 2016;14(1 ):8. doi:10.1186/s12957-015-0757-526758762
   PubMedGoogle Scholar
• Xu Y, Wang B, Zhang F, et al. Long non-coding RNA CCAT2 is associated with poor prognosis in hepatocellular carcinoma and promotes tumor metastasis by regulating snail2-mediated epithelial-mesenchymal transition. Onco Targets Ther. 2017;10:1191–1198. doi:10.2147/OTT.S12710028280353
   PubMed Web of Science ®Google Scholar
• Zeng B, Lin Z, Ye H, et al. Upregulation of LncDQ is Associated with poor prognosis and promotes tumor progression via epigenetic regulation of the EMT Pathway in HCC. Cell Physiol Biochem. 2018;46(3 ):1122–1133. doi:10.1159/00048884129669339
   PubMedGoogle Scholar
• Wu Y, Yuan T, Wang WW, et al. Long noncoding RNA HOST2 promotes epithelial-mesenchymal transition, proliferation, invasion and migration of hepatocellular carcinoma cells by activating the JAK2-STAT3 signaling pathway. Cell Physiol Biochem. 2018;51(1 ):301–314. doi:10.1159/00049523130453302
   PubMedGoogle Scholar
• Xia C, Zhang XY, Liu W, et al. LINC00857 contributes to hepatocellular carcinoma malignancy via enhancing epithelial-mesenchymal transition. J Cell Biochem. 2018.
   Web of Science ®Google Scholar
• Yao Z, Xiong Z, Li R, Liang H, Jia C, Deng M. Long non-coding RNA NRON is downregulated in HCC and suppresses tumour cell proliferation and metastasis. Biomed Pharmacother. 2018;104:102–109. doi:10.1016/j.biopha.2018.05.00629772429
   PubMed Web of Science ®Google Scholar
• Yang J, Li J, Liu B, et al. Long noncoding RNA AK021443 promotes cell proliferation and migration by regulating epithelial-mesenchymal transition in hepatocellular carcinoma cells. DNA Cell Biol. 2018;37(5 ):481–490. doi:10.1089/dna.2017.403029638164
   PubMed Web of Science ®Google Scholar
• Giovannini C, Fornari F, Dallo R, et al. MiR-199-3p replacement affects E-cadherin expression through notch1 targeting in hepatocellular carcinoma. Acta Histochem. 2018;120(2 ):95–102. doi:10.1016/j.acthis.2017.12.00429249451
   PubMed Web of Science ®Google Scholar
• Gou Y, Zhai F, Zhang L, Cui L. RUNX3 regulates hepatocellular carcinoma cell metastasis via targeting miR-186/E-cadherin/EMT pathway. Oncotarget. 2017;8(37 ):61475–61486. doi:10.18632/oncotarget.1842428977878
   PubMedGoogle Scholar
• Tan HX, Wang Q, Chen LZ, et al. MicroRNA-9 reduces cell invasion and E-cadherin secretion in SK-Hep-1 cell. Med Oncol. 2010;27(3 ):654–660. doi:10.1007/s12032-009-9264-219572217
   PubMed Web of Science ®Google Scholar
• Drakaki A, Hatziapostolou M, Polytarchou C, et al. Functional microRNA high throughput screening reveals miR-9 as a central regulator of liver oncogenesis by affecting the PPARA-CDH1 pathway. BMC Cancer. 2015;15:542. doi:10.1186/s12885-015-1584-326206264
   PubMed Web of Science ®Google Scholar
• Kogure T, Kondo Y, Kakazu E, Ninomiya M, Kimura O, Shimosegawa T. Involvement of miRNA-29a in epigenetic regulation of transforming growth factor-beta-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Hepatol Res. 2014;44(8 ):907–919. doi:10.1111/hepr.1218823789939
   PubMed Web of Science ®Google Scholar
• Chang L, Li K, Guo T. miR-26a-5p suppresses tumor metastasis by regulating EMT and is associated with prognosis in HCC. Clin Transl Oncol. 2017;19(6 ):695–703. doi:10.1007/s12094-016-1582-127864783
   PubMed Web of Science ®Google Scholar
• Guo XF, Wang AY, Liu J. HIFs-MiR-33a-twsit1 axis can regulate invasiveness of hepatocellular cancer cells. Eur Rev Med Pharmacol Sci. 2016;20(14 ):3011–3016.27460728
   PubMed Web of Science ®Google Scholar
• Tian Z, Jiang H, Liu Y, et al. MicroRNA-133b inhibits hepatocellular carcinoma cell progression by targeting Sirt1. Exp Cell Res. 2016;343(2 ):135–147. doi:10.1016/j.yexcr.2016.03.02727090017
   PubMed Web of Science ®Google Scholar
• Huang JY, Zhang K, Chen DQ, et al. MicroRNA-451: epithelial-mesenchymal transition inhibitor and prognostic biomarker of hepatocelluar carcinoma. Oncotarget. 2015;6(21 ):18613–18630. doi:10.18632/oncotarget.431726164082
   PubMedGoogle Scholar
• Xia W, Ma X, Li X, et al. miR-153 inhibits epithelial-to-mesenchymal transition in hepatocellular carcinoma by targeting snail. Oncol Rep. 2015;34(2 ):655–662. doi:10.3892/or.2015.400826035427
   PubMed Web of Science ®Google Scholar
• Liu Y, Li Y, Wang R, et al. MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells. J Exp Clin Cancer Res. 2016;35:19. doi:10.1186/s13046-016-0444-626817584
   PubMed Web of Science ®Google Scholar
• Tu K, Zheng X, Dou C, et al. MicroRNA-130b promotes cell aggressiveness by inhibiting peroxisome proliferator-activated receptor gamma in human hepatocellular carcinoma. Int J Mol Sci. 2014;15(11 ):20486–20499. doi:10.3390/ijms15112048625387077
   PubMed Web of Science ®Google Scholar
• Lian J, Jing Y, Dong Q, et al. miR-192, a prognostic indicator, targets the SLC39A6/SNAIL pathway to reduce tumor metastasis in human hepatocellular carcinoma. Oncotarget. 2016;7(3 ):2672–2683. doi:10.18632/oncotarget.660326684241
   PubMedGoogle Scholar
• Xu Q, Zhu Q, Zhou Z, et al. MicroRNA-876-5p inhibits epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by targeting BCL6 corepressor like 1. Biomed Pharmacother. 2018;103:645–652. doi:10.1016/j.biopha.2018.04.03729679906
   PubMed Web of Science ®Google Scholar
• Hung CS, Liu HH, Liu JJ, et al. MicroRNA-200a and −200b mediated hepatocellular carcinoma cell migration through the epithelial to mesenchymal transition markers. Ann Surg Oncol. 2013;20(Suppl 3 ):S360–368. doi:10.1245/s10434-012-2482-422868917
   PubMed Web of Science ®Google Scholar
• Wang J, Yang X, Ruan B, et al. Overexpression of miR-200a suppresses epithelial-mesenchymal transition of liver cancer stem cells. Tumour Biol. 2015;36(4 ):2447–2456. doi:10.1007/s13277-014-2856-225412960
   PubMedGoogle Scholar
• Liu D, Wu J, Liu M, Yin H, He J, Zhang B. Downregulation of miRNA-30c and miR-203a is associated with hepatitis C virus core protein-induced epithelial-mesenchymal transition in normal hepatocytes and hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2015;464(4 ):1215–1221. doi:10.1016/j.bbrc.2015.07.10726210453
   PubMed Web of Science ®Google Scholar
• Wu WL, Wang WY, Yao WQ, Li GD. Suppressive effects of microRNA-16 on the proliferation, invasion and metastasis of hepatocellular carcinoma cells. Int J Mol Med. 2015;36(6 ):1713–1719. doi:10.3892/ijmm.2015.237926499886
   PubMed Web of Science ®Google Scholar
• Ma DN, Chai ZT, Zhu XD, et al. MicroRNA-26a suppresses epithelial-mesenchymal transition in human hepatocellular carcinoma by repressing enhancer of zeste homolog 2. J Hematol Oncol. 2016;9:1. doi:10.1186/s13045-015-0229-y26733151
   PubMed Web of Science ®Google Scholar
• Zhu SM, Chen CM, Jiang ZY, et al. MicroRNA-185 inhibits cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma by targeting six2. Eur Rev Med Pharmacol Sci. 2016;20(9 ):1712–1719.27212161
   PubMed Web of Science ®Google Scholar
• Kim HS, Lee KS, Bae HJ, et al. MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer. Oncotarget. 2015;6(10 ):8089–8102.25797269
   PubMedGoogle Scholar
• Li DP, Fan J, Wu YJ, Xie YF, Zha JM, Zhou XM. MiR-155 up-regulated by TGF-beta promotes epithelial-mesenchymal transition, invasion and metastasis of human hepatocellular carcinoma cells in vitro. Am J Transl Res. 2017;9(6 ):2956–2965.28670383
   PubMed Web of Science ®Google Scholar
• Shen G, Lin Y, Yang X, Zhang J, Xu Z, Jia H. MicroRNA-26b inhibits epithelial-mesenchymal transition in hepatocellular carcinoma by targeting USP9X. BMC Cancer. 2014;14:393. doi:10.1186/1471-2407-14-39324890815
   PubMed Web of Science ®Google Scholar
• Zhang JG, Shi Y, Hong DF, et al. MiR-148b suppresses cell proliferation and invasion in hepatocellular carcinoma by targeting WNT1/beta-catenin pathway. Sci Rep. 2015;5:8087. doi:10.1038/srep0808725627001
   PubMed Web of Science ®Google Scholar
• Zhang JP, Zeng C, Xu L, Gong J, Fang JH, Zhuang SM. MicroRNA-148a suppresses the epithelial-mesenchymal transition and metastasis of hepatoma cells by targeting met/snail signaling. Oncogene. 2014;33(31 ):4069–4076. doi:10.1038/onc.2013.36924013226
   PubMed Web of Science ®Google Scholar
• Wang W, Lin H, Zhou L, et al. MicroRNA-30a-3p inhibits tumor proliferation, invasiveness and metastasis and is downregulated in hepatocellular carcinoma. Eur J Surg Oncol. 2014;40(11 ):1586–1594. doi:10.1016/j.ejso.2013.11.00824290372
   PubMed Web of Science ®Google Scholar
• Han LL, Yin XR, Zhang SQ. miR-103 promotes the metastasis and EMT of hepatocellular carcinoma by directly inhibiting LATS2. Int J Oncol. 2018;53(6 ):2433–2444.30272278
   PubMed Web of Science ®Google Scholar
• Zhao S, Zhang Y, Zheng X, et al. Loss of MicroRNA-101 promotes epithelial to mesenchymal transition in hepatocytes. J Cell Physiol. 2015;230(11 ):2706–2717. doi:10.1002/jcp.2499525808945
   PubMed Web of Science ®Google Scholar
• Zhou Y, Li Y, Ye J, et al. MicroRNA-491 is involved in metastasis of hepatocellular carcinoma by inhibitions of matrix metalloproteinase and epithelial to mesenchymal transition. Liver Int. 2013;33(8 ):1271–1280. doi:10.1111/liv.1219023725476
   PubMed Web of Science ®Google Scholar
• Hou X, Yang L, Jiang X, et al. Role of microRNA-141-3p in the progression and metastasis of hepatocellular carcinoma cell. Int J Biol Macromol. 2019;128:331–339. doi:10.1016/j.ijbiomac.2019.01.14430695725
   PubMed Web of Science ®Google Scholar
• Liang C, Xu Y, Ge H, et al. miR-564 inhibits hepatocellular carcinoma cell proliferation and invasion by targeting the GRB2-ERK1/2-AKT axis. Oncotarget. 2017;8(64 ):107543–107557. doi:10.18632/oncotarget.2250429296185
   PubMedGoogle Scholar
• Gao J, Aksoy BA, Dogrusoz U. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269 ):pl1. doi:10.1126/scisignal.200408823550210
   PubMed Web of Science ®Google Scholar