Epigenetics in hepatoblastoma

Abstract

Hepatoblastoma (HB) is the most frequent pediatric primary liver tumor. When the tumoral lesions can be resected, prognosis is generally favorable. However, there is a significant number of cases in which resection is not possible at diagnosis, and patients usually receive neo-adjuvant cisplatin-based chemotherapy prior to surgery. Unfortunately, some HBs develop resistance to initial chemotherapy or after recurrence, progressing to metastatic disease. Moreover, long-term side effects of chemotherapy remain a serious concern. Understanding the molecular bases of HB development and progression is thus essential for the identification of more efficacious therapies. HBs have a very low mutational burden, and the most frequent mutations occur in the CTNN1B gene (> 80% of cases) and to a lesser extent in NFE2L2 (~10% of cases). These observations suggest that other pathogenic processes besides genetic mutations may play a role in HB tumorigenesis. Epigenetic mechanisms encompass a variety of molecular processes with a tremendous potential to regulate gene expression. They include the covalent modifications of DNA and histones, the activity of enzymatic chromatin remodelers, and the expression of non-coding RNAs. Dysregulation of epigenetic processes has clearly become a hallmark of cancer. Regarding HB, recent studies have explored its epigenetic landscape, the expression of specific epigenetic effectors, and the tumorigenic consequences of epigenetic alterations. The reversible nature of most epigenetic modifications and the possibility to target non-coding RNAs may pave the way for new therapeutic avenues in HB. Here, we summarize and discuss the most relevant findings in this less explored aspect of HB.

Keywords

Hepatoblastoma / molecular mechanisms / epigenetics / therapy

References

[1] Feng J,Heger U,Mehrabi A.Incidence trends and survival prediction of hepatoblastoma in children: a population-based study.Cancer Commun (Lond)2019;39:62 PMCID:PMC6813130

[2] Hiyama E.Pediatric hepatoblastoma: diagnosis and treatment.Transl Pediatr2014;3:293-9 PMCID:PMC4728840

[3] Calvisi DF.Hepatoblastoma: current knowledge and promises from preclinical studies.Transl Gastroenterol Hepatol2020;5:42 PMCID:PMC7063515

[4] Cairo S,Maibach R.A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients.Eur J Cancer2020;141:30-9

[5] Aronson DC,Staalman CR.Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study.J Clin Oncol2005;23:1245-52

[6] Meyers RL,Hiyama E.Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.Lancet Oncol2017;18:122-31 PMCID:PMC5650231

[7] Ranganathan S,Alaggio R.Hepatoblastoma and pediatric hepatocellular carcinoma: an update.Pediatr Dev Pathol2020;23:79-95

[8] Perilongo G,Shafford E.Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma.N Engl J Med2009;361:1662-70

[9] Freyer DR,Chang KW.Prevention of cisplatin-induced ototoxicity in children and adolescents with cancer: a clinical practice guideline.Lancet Child Adolesc Health2020;4:141-50 PMCID:PMC7521149

[10] Marin JJG,Asensio M,Briz O.Mechanisms of anticancer drug resistance in hepatoblastoma.Cancers (Basel)2019;11:407 PMCID:PMC6468761

[11] Jia D,Jing Y.Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex.Hepatology2014;60:1686-96

[12] Eichenmüller M,Kreuder M.The genomic landscape of hepatoblastoma and their progenies with HCC-like features.J Hepatol2014;61:1312-20

[13] Gröbner SN,Weischenfeldt J.ICGC PedBrain-Seq ProjectICGC MMML-Seq ProjectThe landscape of genomic alterations across childhood cancers.Nature2018;555:321-7

[14] Cairo S,De Reyniès A.Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.Cancer Cell2008;14:471-84

[15] Taniguchi K,Aderca IN.Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas.Oncogene2002;21:4863-71

[16] Sumazin P,Treviño LR.Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups.Hepatology2017;65:104-21

[17] Hirsch TZ,Morcrette G.Integrated genomic analysis identifies driver genes and cisplatin-resistant progenitor phenotype in pediatric liver cancer.Cancer Discov2021:candisc

[18] Carrillo-Reixach J,Simon-Coma M.Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.J Hepatol2020;73:328-41

[19] Aretz S,Uhlhaas S.Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations?.Pediatr Blood Cancer2006;47:811-8

[20] Yang A,Gupta A,Geller JI.Germline APC mutations in hepatoblastoma.Pediatr Blood Cancer2018;65:e26892

[21] Zhang Y,Cairo S,Chen X.Molecular mechanisms of hepatoblastoma.Semin Liver Dis2021;41:28-41

[22] Shen G,Zhang J,Liu H.DNA methylation in hepatoblastoma-a literature review.Ital J Pediatr2020;46:113 PMCID:PMC7409486

[23] Claveria-Cabello A,Arechederra M.Epigenetics in liver fibrosis: could HDACs be a therapeutic target?.Cells2020;9:2321 PMCID:PMC7589994

[24] Barcena-Varela M,Fernandez-Barrena MG.Epigenetic mechanisms in hepatic stellate cell activation during liver fibrosis and carcinogenesis.Int J Mol Sci2019;20:2507 PMCID:PMC6566358

[25] Maschietto M,Kashiwabara AY.DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations.Oncotarget2017;8:97871-89 PMCID:PMC5716698

[26] Li X,Sandstedt B,Ekström TJ.Promoter-specific methylation and expression alterations of igf2 and h19 are involved in human hepatoblastoma.Int J Cancer1998;75:176-80

[27] Hartmann W,Koch A.p57KIP2 is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57KIP2, IGF2, and H19.Am J Pathol2000;157:1393-403 PMCID:PMC1850179

[28] Honda S,Haruta M.Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma.Br J Cancer2008;99:1891-9 PMCID:PMC2600691

[29] Kim WY.The regulation of INK4/ARF in cancer and aging.Cell2006;127:265-75

[30] Goel S,McAllister SS.CDK4/6 inhibition in cancer: beyond cell cycle arrest.Trends Cell Biol2018;28:911-25 PMCID:PMC6689321

[31] Zang JJ,Xu JF.P16 gene hypermethylation and hepatocellular carcinoma: a systematic review and meta-analysis.World J Gastroenterol2011;17:3043-8 PMCID:PMC3132256

[32] Sterlacci W,Veits L.A comprehensive analysis of p16 expression, gene status, and promoter hypermethylation in surgically resected non-small cell lung carcinomas.J Thorac Oncol2011;6:1649-57

[33] Qu Y,Hou P.Gene methylation in gastric cancer.Clin Chim Acta2013;424:53-65

[34] Shim YH,Choi MS.Hypermethylation of the p16 gene and lack of p16 expression in hepatoblastoma.Mod Pathol2003;16:430-6

[35] Harada K,Maitra A.Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines.Oncogene2002;21:4345-9

[36] Malpeli G,Decimo I.Methylation dynamics of RASSF1A and its impact on cancer.Cancers (Basel)2019;11:959 PMCID:PMC6678546

[37] Hesson LB,Latif F.The role of RASSF1A methylation in cancer.Dis Markers2007;23:73-87 PMCID:PMC3850810

[38] Khokhlatchev A,Xavier R.Identification of a novel Ras-regulated proapoptotic pathway.Current Biology2002;12:253-65

[39] Law J,Zare A.Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.J Biol Chem2015;290:24100-18 PMCID:PMC4591801

[40] Baksh S,Fenton S.The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death.Mol Cell2005;18:637-50

[41] Fenton SL,Agathanggelou A.Identification of the E1A-regulated transcription factor p120 E4F as an interacting partner of the RASSF1A candidate tumor suppressor gene.Cancer Res2004;64:102-7

[42] Zhang YJ,Chen Y.High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1-DNA adduct levels in human hepatocellular carcinoma.Mol Carcinog2002;35:85-92

[43] Wong IH,Wong J.Ubiquitous aberrant RASSF1A promoter methylation in childhood neoplasia.Clin Cancer Res2004;10:994-1002

[44] Villanueva A,Sayols S.HEPTROMIC ConsortiumDNA methylation-based prognosis and epidrivers in hepatocellular carcinoma.Hepatology2015;61:1945-56

[45] Wong N,Tsang K,To K.Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma.J Hepatol2002;37:633-9

[46] Yang B,Guo M,Clark DP.Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma.Mod Pathol2005;18:412-20

[47] Chen YJ,Zou SQ.Inactivation of RASSF1A, the tumor suppressor gene at 3p21.3 in extrahepatic cholangiocarcinoma.World J Gastroenterol2005;11:1333-8 PMCID:PMC4250680

[48] Sugawara W,Sasaki F.Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma.Pediatr Blood Cancer2007;49:240-9

[49] Honda S,Sugawara W.The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients.Int J Cancer2008;123:1117-25

[50] Honda S,Suzuki H.RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients.Pediatr Surg Int2013;29:1147-52

[51] Yeo W,Wong WL,Zhong S.High frequency of promoter hypermethylation of RASSF1A in tumor and plasma of patients with hepatocellular carcinoma.Liver Int2005;25:266-72

[52] Liu G,Zheng S,Dong R.Aberrant RASSF5 gene transcribed region hypermethylation in pediatric hepatoblastomas.Int J Clin Exp Pathol2018;11:3612-7 PMCID:PMC6962826

[53] Sprynski AC,Kassambara A.Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation.Leukemia2010;24:1940-50 PMCID:PMC3141222

[54] Enguita-Germán M.Targeting the insulin-like growth factor pathway in hepatocellular carcinoma.World J Hepatol2014;6:716-37 PMCID:PMC4209417

[55] Abdel-Rahman O.Insulin-like growth factor pathway aberrations and gastric cancer; evaluation of prognostic significance and assessment of therapeutic potentials.Med Oncol2015;32:431

[56] Dziadziuszko R,Hirsch FR.The insulin-like growth factor pathway in lung cancer.J Thorac Oncol2008;3:815-8

[57] Nitulescu GM,Nitulescu G.The Akt pathway in oncology therapy and beyond (Review).Int J Oncol2018;53:2319-31 PMCID:PMC6203150

[58] Gray SG,Ekström C.Altered expression of members of the IGF-axis in hepatoblastomas.Br J Cancer2000;82:1561-7 PMCID:PMC2363389

[59] Rumbajan JM,Souzaki R.Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma.BMC Cancer2013;13:608 PMCID:PMC3880457

[60] Bach LA.IGF-binding proteins.J Mol Endocrinol2018;61:T11-28

[61] Akmal SN,Maclay J,Ikeda T.Insulin-like growth factor 2 and insulin-like growth factor binding protein 2 expression in hepatoblastoma.Human Pathology1995;26:846-51

[62] Williams AC,Perks CM.Increased p53-dependent apoptosis by the insulin-like growth factor binding protein IGFBP-3 in human colonic adenoma-derived cells.Cancer Res2000;60:22-7

[63] Buckbinder L,Velasco-Miguel S.Induction of the growth inhibitor IGF-binding protein 3 by p53.Nature1995;377:646-9

[64] Hanafusa T,Shiraha H.Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation.BMC Cancer2005;5:9 PMCID:PMC548269

[65] López-Terrada D,Finegold MJ.Hep G2 is a hepatoblastoma-derived cell line.Hum Pathol2009;40:1512-5

[66] Hanafusa T,Nouso K.Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma.Cancer Letters2002;176:149-58

[67] Tomii K,Toyooka S.Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers.Int J Cancer2007;120:566-73

[68] Regel I,Joppien S.IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors.Mol Cancer2012;11:9 PMCID:PMC3349592

[69] Nagai H,Terada Y.Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas.J Hum Genet2003;48:65-9

[70] Brooks AJ.JAK-STAT signalling pathway in cancer.Cancers (Basel)2020;12:1971 PMCID:PMC7409105

[71] Bagnyukova TV,Muskhelishvili L,Beland FA.Epigenetic downregulation of the suppressor of cytokine signaling 1 (Socs1) gene is associated with the STAT3 activation and development of hepatocellular carcinoma induced by methyl-deficiency in rats.Cell Cycle2008;7:3202-10

[72] Huang FJ,Price JE.Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis.Cancer Res2008;68:9634-42 PMCID:PMC7418219

[73] Zhang J,Yu JP,Ren XB.Role of SOCS1 in tumor progression and therapeutic application.Int J Cancer2012;130:1971-80

[74] Raccurt M,Lau P.Suppressor of cytokine signalling gene expression is elevated in breast carcinoma.Br J Cancer2003;89:524-32 PMCID:PMC2394374

[75] Guenterberg KD,Mundy-Bosse BL.Enhanced anti-tumor activity of interferon-alpha in SOCS1-deficient mice is mediated by CD4⁺ and CD8⁺ T cells.Cancer Immunol Immunother2011;60:1281-8 PMCID:PMC3521522

[76] Zimmerer JM,Kondadasula SV.IFN-alpha-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins.J Immunol2007;178:4832-45

[77] Sakamoto LH,Cajaiba M,Vettore AL.MT1G hypermethylation: a potential prognostic marker for hepatoblastoma.Pediatr Res2010;67:387-93

[78] Tomlinson GE.Genetics and epigenetics of hepatoblastoma.Pediatr Blood Cancer2012;59:785-92

[79] Russell JO.Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology.Annu Rev Pathol2018;13:351-78 PMCID:PMC5927358

[80] Gao L,Zhang P,Yang T.Role of canonical Hedgehog signaling pathway in liver.Int J Biol Sci2018;14:1636-44 PMCID:PMC6216024

[81] Zheng X,Gai X.Role of the Hedgehog pathway in hepatocellular carcinoma (review).Oncol Rep2013;30:2020-6

[82] Wang LH,Hua XY.Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions.Mod Pathol2006;19:675-83

[83] Tada M,Tanaka Y.Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma.Clin Cancer Res2008;14:3768-76

[84] Eichenmüller M,Hagl B.Blocking the hedgehog pathway inhibits hepatoblastoma growth.Hepatology2009;49:482-90

[85] Xu X,Sun X.Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression.Oncotarget2015;6:26161-76 PMCID:PMC4694893

[86] Kim YJ,Kim JT.NDRG2 expression decreases with tumor stages and regulates TCF/beta-catenin signaling in human colon carcinoma.Carcinogenesis2009;30:598-605 PMCID:PMC2664458

[87] Lusis EA,Chicoine MR.Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma.Cancer Res2005;65:7121-6

[88] Gödeke J,Trippel F.Low expression of N-myc downstream-regulated gene 2 (NDRG2) correlates with poor prognosis in hepatoblastoma.Hepatol Int2016;10:370-6

[89] Baharudin R,Lee LH.Epigenetics of SFRP1: the dual roles in human cancers.Cancers (Basel)2020;12:445 PMCID:PMC7072595

[90] Zhao CH,Zhang N.Hypermethylation and aberrant expression of Wnt antagonist secreted frizzled-related protein 1 in gastric cancer.World J Gastroenterol2007;13:2214-7 PMCID:PMC4146847

[91] Wang X,Bu R,Zhao C.Methylation and aberrant expression of the Wnt antagonist secreted Frizzled-related protein 1 in bladder cancer.Oncol Lett2012;4:334-8 PMCID:PMC3402742

[92] Taguchi YH,Umeyama H.SFRP1 is a possible candidate for epigenetic therapy in non-small cell lung cancer.BMC Med Genomics2016;9 Suppl 1:28 PMCID:PMC4989892

[93] Kim J.In silico identification of SFRP1 as a hypermethylated gene in colorectal cancers.Genomics Inform2014;12:171-80 PMCID:PMC4330251

[94] Shih YL,Hsieh CB.Promoter methylation of the secreted frizzled-related protein 1 gene SFRP1 is frequent in hepatocellular carcinoma.Cancer2006;107:579-90

[95] Regel I,Mahajan UM.Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations.J Cancer Res Clin Oncol2020;146:1153-67 PMCID:PMC7142044

[96] Shih YL,Lai HC.SFRP1 suppressed hepatoma cells growth through Wnt canonical signaling pathway.Int J Cancer2007;121:1028-35

[97] Honda S,Suzuki H.Clinical prognostic value of DNA methylation in hepatoblastoma: four novel tumor suppressor candidates.Cancer Sci2016;107:812-9 PMCID:PMC4968605

[98] Rivas MP,Maschietto M.Hepatoblastomas exhibit marked NNMT downregulation driven by promoter DNA hypermethylation.Tumour Biol2020;42:1010428320977124

[99] Li S,Yang Z.Prognostic value of nicotinamide N-methyltransferase expression in patients with solid tumors: a systematic review and meta-analysis.Front Physiol2018;9:1407 PMCID:PMC6187113

[100] Ulanovskaya OA,Cravatt BF.NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink.Nat Chem Biol2013;9:300-6 PMCID:PMC3631284

[101] Fujiyoshi S,Minato M.Hypermethylation of CSF3R is a novel cisplatin resistance marker and predictor of response to postoperative chemotherapy in hepatoblastoma.Hepatol Res2020;50:598-606

[102] Zynger DL,Luan C,Yang GY.Expression of glypican 3 in hepatoblastoma: an immunohistochemical study of 65 cases.Hum Pathol2008;39:224-30

[103] Nguyen LH,Seligson MT.Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.Cancer Cell2014;26:248-61 PMCID:PMC4145706

[104] Meng W,Bai Z.The immunosuppression role of alpha-fetoprotein in human hepatocellular carcinoma.Discov Med2016;21:489-94

[105] Cui X,Zheng S,Dong R.Genome-wide analysis of DNA methylation in hepatoblastoma tissues.Oncol Lett2016;12:1529-34 PMCID:PMC4950688

[106] Fuhrman-Luck RA,Stephens CR,Clements JA.Prostate cancer-associated kallikrein-related peptidase 4 activates matrix metalloproteinase-1 and thrombospondin-1.J Proteome Res2016;15:2466-78

[107] Wang P,Seidl C.Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer.Br J Cancer2018;119:1-9 PMCID:PMC6189062

[108] Kontos CK,Papadopoulos IN.Kallikrein-related peptidase 4 (KLK4) mRNA predicts short-term relapse in colorectal adenocarcinoma patients.Cancer Lett2013;330:106-12

[109] Liu B,Zheng S,Dong R.Aberrant KLK4 gene promoter hypomethylation in pediatric hepatoblastomas.Oncol Lett2017;13:1360-4 PMCID:PMC5403249

[110] Vita M.The Myc oncoprotein as a therapeutic target for human cancer.Semin Cancer Biol2006;16:318-30

[111] Kress TR,Amati B.MYC: connecting selective transcriptional control to global RNA production.Nat Rev Cancer2015;15:593-607

[112] Eberherr C,Vokuhl C.Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells.Int J Oncol2019;54:1853-63

[113] Barcena-Varela M,Alvarez L.Epigenetic mechanisms and metabolic reprogramming in fibrogenesis: dual targeting of G9a and DNMT1 for the inhibition of liver fibrosis.Gut2021;70:388-400

[114] Bárcena-Varela M,Llerena S.Dual targeting of histone methyltransferase G9a and DNA-methyltransferase 1 for the treatment of experimental hepatocellular carcinoma.Hepatology2019;69:587-603

[115] Ding WJ,Chen XY.The expression and clinical significance of DNA methyltransferase proteins in human gastric cancer.Dig Dis Sci2008;53:2083-9

[116] Tzelepi V,Efstathiou E.Epigenetics and prostate cancer: defining the timing of DNA methyltransferase deregulation during prostate cancer progression.Pathology2020;52:218-27

[117] Colyn L,Álvarez-Sola G.Dual targeting of G9a and DNA Methyltransferase-1 for the treatment of experimental cholangiocarcinoma.Hepatology2021;73:2380-96

[118] Li A,Hong SM.Pancreatic cancer DNMT1 expression and sensitivity to DNMT1 inhibitors.Cancer Biol Ther2010;9:321-9 PMCID:PMC2920347

[119] Rivas MP,Fernandes GR.TET upregulation leads to 5-hydroxymethylation enrichment in hepatoblastoma.Front Genet2019;10:553 PMCID:PMC6582250

[120] Huang Y.Connections between TET proteins and aberrant DNA modification in cancer.Trends Genet2014;30:464-74 PMCID:PMC4337960

[121] Lin G,Yang Z,Liu H.Hypoxia induces the expression of TET enzymes in HepG2 cells.Oncol Lett2017;14:6457-62 PMCID:PMC5686438

[122] Liu C,Chen X.Decrease of 5-hydroxymethylcytosine is associated with progression of hepatocellular carcinoma through downregulation of TET1.PLoS One2013;8:e62828 PMCID:PMC3650038

[123] Sidhu H.UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics.Tumour Biol2017;39:1010428317692205

[124] Jin W,Chen Y.UHRF1 is associated with epigenetic silencing of BRCA1 in sporadic breast cancer.Breast Cancer Res Treat2010;123:359-73

[125] Sabatino L,Pancione M.UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression.Oncogene2012;31:5061-72

[126] Zhuo H,Lin Z.The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellular carcinoma.Mol Carcinog2016;55:209-19

[127] Ying L,Qiu F.Epigenetic repression of regulator of G-protein signaling 2 by ubiquitin-like with PHD and ring-finger domain 1 promotes bladder cancer progression.FEBS J2015;282:174-82

[128] Zhou L,Jin Z.UHRF1 promotes proliferation of gastric cancer via mediating tumor suppressor gene hypermethylation.Cancer Biol Ther2015;16:1241-51 PMCID:PMC4622020

[129] Beck A,Wagner A.Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma.Clin Epigenetics2018;10:27 PMCID:PMC5833129

[130] Dawson MA.Cancer epigenetics: from mechanism to therapy.Cell2012;150:12-27

[131] Gray SG,Eriksson T.Expression of genes involved with cell cycle control, cell growth and chromatin modification are altered in hepatoblastomas.Int J Mol Med2000;6:161-9

[132] Kuo P,Lin C.Resveratrol- induced apoptosis is mediated by p53-dependent pathway in Hep G2 cells.Life Sciences2002;72:23-34

[133] West AC.New and emerging HDAC inhibitors for cancer treatment.J Clin Invest2014;124:30-9 PMCID:PMC3871231

[134] Singh AK,Pandey AK.Targeting histone deacetylases with natural and synthetic agents: an emerging anticancer strategy.Nutrients2018;10:731 PMCID:PMC6024317

[135] Venturelli S,Böcker A.Resveratrol as a pan-HDAC inhibitor alters the acetylation status of histone [corrected] proteins in human-derived hepatoblastoma cells.PLoS One2013;8:e73097 PMCID:PMC3758278

[136] Beck A,Hagemann M.Connectivity map identifies HDAC inhibition as a treatment option of high-risk hepatoblastoma.Cancer Biol Ther2016;17:1168-76 PMCID:PMC5137489

[137] French C. Small-molecule targeting of BET proteins in cancer. Elsevier; 2016. p. 21-58.

[138] Wang YH,Sui YN.BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway.Oncol Lett2015;10:2227-32 PMCID:PMC4579919

[139] Saltsman JA,Narayan NJC.A human organoid model of aggressive hepatoblastoma for disease modeling and drug testing.Cancers (Basel)2020;12:2668 PMCID:PMC7563272

[140] Chen Y,Yang J.The role of histone methylation in the development of digestive cancers: a potential direction for cancer management.Signal Transduct Target Ther2020;5:143 PMCID:PMC7398912

[141] Kim KH.Targeting EZH2 in cancer.Nat Med2016;22:128-34 PMCID:PMC4918227

[142] Wang Y,Chen K.Enhancer of zeste homolog 2 depletion arrests the proliferation of hepatoblastoma cells.Mol Med Rep2016;13:2724-8

[143] Schlachter K,Halász J.High tricellulin expression is associated with better survival in human hepatoblastoma.Histopathology2014;65:631-41

[144] Wong LS.Decoding the roles of long noncoding RNAs in hepatocellular carcinoma.Int J Mol Sci2021;22:3137 PMCID:PMC8003515

[145] Syeda Z, Langden SSS, Munkhzul C, Lee M, Song SJ. Regulatory mechanism of microRNA expression in cancer.Int J Mol Sci2020;21:1723 PMCID:PMC7084905

[146] Iorio MV.MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. a comprehensive review.EMBO Mol Med2012;4:143-59 PMCID:PMC3376845

[147] Magrelli A,Salvatore M.Altered microRNA expression patterns in hepatoblastoma patients.Transl Oncol2009;2:157-63 PMCID:PMC2730135

[148] Gyugos M,Kenessey I.MicroRNA expression might predict prognosis of epithelial hepatoblastoma.Virchows Arch2014;464:419-27

[149] Ecevit ÇÖ,Tosun Yildirim H.MicroRNA-17, microRNA-19b, microRNA-146a, microRNA-302d expressions in hepatoblastoma and clinical importance.J Pediatr Hematol Oncol2019;41:7-12

[150] Zatkova A,Hartmann W.Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma.Genes Chromosomes Cancer2004;39:126-37

[151] Voz ML,Hensen K.Microarray screening for target genes of the proto-oncogene PLAG1.Oncogene2004;23:179-91

[152] Frowein J, Pagel P, Kappler R, von Schweinitz D, Roscher A, Schmid I. MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma.Hepatology2011;53:833-42

[153] von Frowein J,Kappler R.MiR-492 regulates metastatic properties of hepatoblastoma via CD44.Liver Int2018;38:1280-91

[154] Yin DT,Li M.DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma.Endocr Relat Cancer2013;20:507-14

[155] Veeck J,Fuchs T.Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer.BMC Cancer2009;9:217 PMCID:PMC2717119

[156] Li Q,Zhao Y,Liu J.MiR-92b inhibitor promoted glioma cell apoptosis via targeting DKK3 and blocking the Wnt/beta-catenin signaling pathway.J Transl Med2013;11:302 PMCID:PMC4028874

[157] Farkas SA,Vodickova L,Nilsson TK.DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/β-catenin signaling pathway genes.Epigenomics2014;6:179-91

[158] Pei Y,Iijima T,Inadome Y.Overexpression of Dickkopf 3 in hepatoblastomas and hepatocellular carcinomas.Virchows Arch2009;454:639-46

[159] Pei Y,Yuan S.GATA4 promotes hepatoblastoma cell proliferation by altering expression of miR125b and DKK3.Oncotarget2016;7:77890-901 PMCID:PMC5363629

[160] Cairo S,de Reyniès A.Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer.Proc Natl Acad Sci U S A2010;107:20471-6 PMCID:PMC2996672

[161] Weiss JBW,Eberherr C.High expression of IGF2-derived intronic miR-483 predicts outcome in hepatoblastoma.Cancer Biomark2020;28:321-8

[162] Cartier F,Lesjean S.New tumor suppressor microRNAs target glypican-3 in human liver cancer.Oncotarget2017;8:41211-26 PMCID:PMC5522324

[163] Samuels-lev Y,Bergamaschi D.ASPP proteins specifically stimulate the apoptotic function of p53.Molecular Cell2001;8:781-94

[164] Liang B,Song S.ASPP2 inhibits tumor growth by repressing the mevalonate pathway in hepatocellular carcinoma.Cell Death Dis2019;10:830 PMCID:PMC6828733

[165] Liu L,Li X.Effect of miR-21 on apoptosis in hepatoblastoma cell through activating ASPP2/p38 signaling pathway in vitro and in vivo.Artif Cells Nanomed Biotechnol2019;47:3729-36

[166] Honda S,Leichter AL.A microRNA cluster in the DLK1-DIO3 imprinted region on chromosome 14q32.2 is dysregulated in metastatic hepatoblastomas.Front Oncol2020;10:513601 PMCID:PMC7689214

[167] Chen LJ,Ji CY.Long non-coding RNA CRNDE regulates angiogenesis in hepatoblastoma by targeting the MiR-203/VEGFA axis.Pathobiology2020;87:161-70

[168] Song H,Li HY.Characterization of hsa_circ_0000594 as a new biomarker and therapeutic target for hepatoblastoma.Eur Rev Med Pharmacol Sci2019;23:8274-86

[169] Zhen N,Ma J.CircHMGCS1 promotes hepatoblastoma cell proliferation by regulating the IGF signaling pathway and glutaminolysis.Theranostics2019;9:900-19 PMCID:PMC6376477

[170] Liu Y,Liu Y,Wang X.Transcription activation of circ-STAT3 induced by Gli2 promotes the progression of hepatoblastoma via acting as a sponge for miR-29a/b/c-3p to upregulate STAT3/Gli2.J Exp Clin Cancer Res2020;39:101 PMCID:PMC7268652

[171] Galardi A,Di Paolo V.Exosomal miRNAs in pediatric cancers.Int J Mol Sci2019;20:4600 PMCID:PMC6770697

[172] Jiao C,Zhu A,Xu X.Exosomal miR-34s panel as potential novel diagnostic and prognostic biomarker in patients with hepatoblastoma.J Pediatr Surg2017;52:618-24

[173] Nandwani A,Datta M.LncRNAs in cancer: regulatory and therapeutic implications.Cancer Lett2021;501:162-71

[174] Bach DH.Long noncoding RNAs in cancer cells.Cancer Lett2018;419:152-66

[175] Dong R,Xue P.Genome-wide analysis of long noncoding RNA (lncRNA) expression in hepatoblastoma tissues.PLoS One2014;9:e85599 PMCID:PMC3894996

[176] Wang XD,Zhou CY.Potential therapies for residual hepatoblastoma following incomplete ablation treatment in a nude mouse subcutaneous xenograft model based on lncRNA and mRNA expression profiles.Oncol Rep2020;43:1915-27 PMCID:PMC7160554

[177] Alipoor B,Sabati Z,Ghasemi H.An updated review of the H19 lncRNA in human cancer: molecular mechanism and diagnostic and therapeutic importance.Mol Biol Rep2020;47:6357-74

[178] Li J,An G.LncRNA TUG1 acts as a tumor suppressor in human glioma by promoting cell apoptosis.Exp Biol Med (Maywood)2016;241:644-9 PMCID:PMC4950328

[179] Zhang EB,Sun M.P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression.Cell Death Dis2014;5:e1243 PMCID:PMC4047917

[180] Fan S,Ke Z.Downregulation of the long non-coding RNA TUG1 is associated with cell proliferation, migration, and invasion in breast cancer.Biomed Pharmacother2017;95:1636-43

[181] Ma B,Zhang L.Upregulation of long non-coding RNA TUG1 correlates with poor prognosis and disease status in osteosarcoma.Tumour Biol2016;37:4445-55

[182] Zhai HY,Yu X.Overexpression of long non-coding RNA TUG1 promotes colon cancer progression.Med Sci Monit2016;22:3281-7 PMCID:PMC5027858

[183] Huang MD,Qi FZ.Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2.Mol Cancer2015;14:165 PMCID:PMC4558931

[184] Dong R,Liu BH.Targeting long non-coding RNA-TUG1 inhibits tumor growth and angiogenesis in hepatoblastoma.Cell Death Dis2016;7:e2278 PMCID:PMC5108331

[185] Zhang J,Peng G.CRNDE: an important oncogenic long non-coding RNA in human cancers.Cell Prolif2018;51:e12440 PMCID:PMC6528921

[186] Dong R,Zhang BB,Zheng S.Long non-coding RNA-CRNDE: a novel regulator of tumor growth and angiogenesis in hepatoblastoma.Oncotarget2017;8:42087-97 PMCID:PMC5522051

[187] Lv B,Miao R.Comprehensive analysis and experimental verification of LINC01314 as a tumor suppressor in hepatoblastoma.Biomed Pharmacother2018;98:783-92

[188] Yu Q,Peng S,Qin X.Exosomal-mediated transfer of OIP5-AS1 enhanced cell chemoresistance to trastuzumab in breast cancer via up-regulating HMGB3 by sponging miR-381-3p.Open Med (Wars)2021;16:512-25 PMCID:PMC8010158

[189] Zhang Z,Yang F.Kockdown of OIP5-AS1 expression inhibits proliferation, metastasis and EMT progress in hepatoblastoma cells through up-regulating miR-186a-5p and down-regulating ZEB1.Biomed Pharmacother2018;101:14-23

[190] Li A,Niu X,Li B.Downregulation of OIP5-AS1 affects proNGF-induced pancreatic cancer metastasis by inhibiting p75NTR levels.Aging (Albany NY)2021;13:10688-702 PMCID:PMC8064169

[191] Wang X,Zhao R,Yang G.STAT3-activated long non-coding RNA lung cancer associated transcript 1 drives cell proliferation, migration, and invasion in hepatoblastoma through regulation of the miR-301b/STAT3 axis.Hum Gene Ther2019;30:702-13

[192] Cui X,Liu L.The long non-coding RNA ZFAS1 sponges miR-193a-3p to modulate hepatoblastoma growth by targeting RALY via HGF/c-Met pathway.Front Cell Dev Biol2019;7:271 PMCID:PMC6856658

[193] Burenina OY,Kustova IF.Panel of potential lncRNA biomarkers can distinguish various types of liver malignant and benign tumors.J Cancer Res Clin Oncol2021;147:49-59

[194] Jiao S,Huang S,Gao B.Advances in the identification of circular RNAs and research into circRNAs in human diseases.Front Genet2021;12:665233 PMCID:PMC8017306

[195] Hansen TB,Clausen BH.Natural RNA circles function as efficient microRNA sponges.Nature2013;495:384-8

[196] Yang Y,Mao M.Extensive translation of circular RNAs driven by N⁶-methyladenosine.Cell Res2017;27:626-41 PMCID:PMC5520850

[197] Li Z,Bao C.Exon-intron circular RNAs regulate transcription in the nucleus.Nat Struct Mol Biol2015;22:256-64

[198] Conn VM,Nayak A.A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation.Nat Plants2017;3:17053

[199] Zhong Z,Chen J.Screening differential circular RNA expression profiles reveals the regulatory role of circTCF25-miR-103a-3p/miR-107-CDK6 pathway in bladder carcinoma.Sci Rep2016;6:30919 PMCID:PMC4971518

[200] Li P,Chen H.Using circular RNA as a novel type of biomarker in the screening of gastric cancer.Clin Chim Acta2015;444:132-6

[201] Tang Y,Jiang HM.The roles of circRNAs in liver cancer immunity.Front Oncol2020;10:598464 PMCID:PMC7890029

[202] Liu BH,Liu XQ,Dong KR.Expression profiling identifies circular RNA signature in hepatoblastoma.Cell Physiol Biochem2018;45:706-19

[203] Lee H,Noh SJ.Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma.Hum Pathol2011;42:204-13

[204] Zhang ZY,Nam SH.SIRT1 regulates oncogenesis via a mutant p53-dependent pathway in hepatocellular carcinoma.J Hepatol2015;62:121-30

[205] Matés JM,Santos-Jiménez JL.Dysregulation of glutaminase and glutamine synthetase in cancer.Cancer Lett2019;467:29-39

[206] Chen L,Wu Y.CircRNA CDR1as promotes hepatoblastoma proliferation and stemness by acting as a miR-7-5p sponge to upregulate KLF4 expression.Aging (Albany NY)2020;12:19233-53 PMCID:PMC7732296

[207] Zhao BS,He C.Post-transcriptional gene regulation by mRNA modifications.Nat Rev Mol Cell Biol2017;18:31-42 PMCID:PMC5167638

[208] Dominissini D,Schwartz S.Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.Nature2012;485:201-6

[209] Wang X,Gomez A.N6-methyladenosine-dependent regulation of messenger RNA stability.Nature2014;505:117-20 PMCID:PMC3877715

[210] Xu Y,Shen F.YTH domain proteins: a family of m⁶A readers in cancer progression.Front Oncol2021;11:629560 PMCID:PMC7937903

[211] Chen M,Law CT.RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2.Hepatology2018;67:2254-70

[212] Liu L,Sun G.m⁶A mRNA methylation regulates CTNNB1 to promote the proliferation of hepatoblastoma.Mol Cancer2019;18:188 PMCID:PMC6927193

[213] Cui X,Li J.Cross talk between RNA N6-methyladenosine methyltransferase-like 3 and miR-186 regulates hepatoblastoma progression through Wnt/β-catenin signalling pathway.Cell Prolif2020;53:e12768 PMCID:PMC7106953

[214] Zhuo ZJ,Chen Z.WTAP gene variants confer hepatoblastoma susceptibility: a seven-center case-control study.Mol Ther Oncolytics2020;18:118-25 PMCID:PMC7338985

[215] Han L,Yu S.The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers.Cancer Cell2015;28:515-28 PMCID:PMC4605878

[216] Paz-Yaacov N,Buchumenski I.Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors.Cell Rep2015;13:267-76

[217] Galeano F,Rossetti C.Human BLCAP transcript: new editing events in normal and cancerous tissues.Int J Cancer2010;127:127-37 PMCID:PMC2958456

[218] Feng S.Clinical advances in targeting epigenetics for cancer therapy.FEBS J2021;

[219] El Sayed S, Cristante J, Guyon L, Denis J, Chabre O, Cherradi N. MicroRNA Therapeutics in cancer: current advances and challenges.Cancers (Basel)2021;13:2680 PMCID:PMC8198729

[220] Oronsky B,Knox S,Scicinski J.Episensitization: therapeutic tumor resensitization by epigenetic agents: a review and reassessment.Anticancer Agents Med Chem2014;14:1121-7 PMCID:PMC4262965

[221] Oronsky BT,Lybeck M.Episensitization: defying time's arrow.Front Oncol2015;5:134 PMCID:PMC4464068

[222] Li GH,Qi TT.Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance.J Exp Clin Cancer Res2021;40:174 PMCID:PMC8132395

[223] Yang T,Wang Y.Predictive biomarkers and potential drug combinations of epi-drugs in cancer therapy.Clin Epigenetics2021;13:113 PMCID:PMC8130364

[224] Wei QY,Lau ATY.Recent Progress of Nanocarrier-Based Therapy for Solid Malignancies.Cancers (Basel)2020;12:2783 PMCID:PMC7600685

[225] Subhan MA,Torchilin VP.Advances in siRNA delivery strategies for the treatment of MDR cancer.Life Sci2021;274:119337