Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy
2018; Elsevier BV; Volume: 156; Issue: 2 Linguagem: Inglês
10.1053/j.gastro.2018.11.001
ISSN1528-0012
AutoresRenumathy Dhanasekaran, Jean–Charles Nault, Lewis R. Roberts, Jessica Zucman‐Rossi,
Tópico(s)Cholangiocarcinoma and Gallbladder Cancer Studies
ResumoThe pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer. The pathogenesis of hepatocellular carcinoma (HCC) is poorly understood, but recent advances in genomics have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors, such as aflatoxin, cause liver cancer. Genetic analyses of liver tissues from patients have provided important information about tumor initiation and progression. Findings from these studies can potentially be used to individualize the management of HCC. In addition to sorafenib, other multi-kinase inhibitors have been approved recently for treatment of HCC, and the preliminary success of immunotherapy has raised hopes. Continued progress in genomic medicine could improve classification of HCCs based on their molecular features and lead to new treatments for patients with liver cancer. Jean-Charles NaultView Large Image Figure ViewerDownload Hi-res image Download (PPT)Lewis R. RobertsView Large Image Figure ViewerDownload Hi-res image Download (PPT)Jessica Zucman-RossiView Large Image Figure ViewerDownload Hi-res image Download (PPT) Hepatocellular carcinoma (HCC) is the second-most common cause of cancer mortality worldwide.1Ferlay J. Soerjomataram I. Dikshit R. et al.Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2014; 136: E359-E386Crossref PubMed Scopus (5) Google Scholar HCC is most commonly caused by chronic hepatitis or cirrhosis, resulting from infection with hepatitis B virus (HBV) and C virus (HCV), as well as alcoholic or fatty liver diseases. However, the attributable risks from different etiologies vary significantly among regions. HBV is the most common risk factor for HCC in Southeast Asia and sub-Saharan Africa,2Chen W. Zheng R. Baade P.D. et al.Cancer statistics in China, 2015.CA Cancer J Clin. 2016; 66: 115-132Crossref PubMed Scopus (4753) Google Scholar, 3Acharya S.K. Epidemiology of hepatocellular carcinoma in India.J Clin Exp Hepatol. 2014; 4: S27-S33Abstract Full Text Full Text PDF PubMed Google Scholar, 4Yi S.-W. Choi J.-S. Yi J.-J. et al.Risk factors for hepatocellular carcinoma by age, sex, and liver disorder status: a prospective cohort study in Korea.Cancer. 2018; 124: 2748-2757Crossref PubMed Scopus (5) Google Scholar whereas HCV infection is the most common risk factor in Egypt,5Gomaa A. Allam N. Elsharkawy A. et al.Hepatitis C infection in Egypt: prevalence, impact and management strategies.Hepat Med. 2017; 9: 17-25Crossref PubMed Google Scholar Europe,6Blachier M. Leleu H. Peck-Radosavljevic M. et al.The burden of liver disease in Europe: a review of available epidemiological data.J Hepatol. 2013; 58: 593-608Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar North America,7Ryerson A.B. Eheman C.R. Altekruse S.F. et al.Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer.Cancer. 2016; 122: 1312-1337Crossref PubMed Scopus (318) Google Scholar and Japan.8Umemura T. Ichijo T. Yoshizawa K. et al.Epidemiology of hepatocellular carcinoma in Japan.J Gastroenterol. 2009; 44: 102-107Crossref PubMed Scopus (0) Google Scholar Despite the magnitude of the global burden of HCC, it is one of the least understood cancers and has limited therapeutic options. Advances in genomic research have increased our understanding of HCC development, and could lead to new strategies for prevention and therapy. We review the genomic features of HCC, correlations between genotypes and phenotypes, progression of viral hepatitis-related HCC, and strategies to individualize treatment. Over the past decade, the study of cancer has shifted from evaluation of variants of individual genes and pathways to analyses of gene expression patterns and epigenetic profiles of tumor tissues and cells. Advances in next-generation sequencing and computational data analyses can be credited for this shift. The genetic events that contribute to HCC initiation and progression can be classified as genomic (somatic mutations and genome structure changes, such as gene fusions or copy number variations), epigenetic (changes in methylation, chromatin remodeling, microRNAs, and long noncoding [lnc] RNAs), and transcriptional (changes in gene expression) (Figure 1). Somatic mutations occur in somatic (non-germ) cells and are therefore not heritable. When these mutations occur in proto-oncogenes or tumor suppressor genes or in genes involved in regulatory pathways, they can lead to cell transformation and tumorigenesis. Whole-exome and whole-genome sequencing studies have identified mutations that contribute to development of HCC.9Fujimoto A. Totoki Y. Abe T. et al.Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators.Nat Genet. 2012; 44: 760-764Crossref PubMed Scopus (472) Google Scholar, 10Guichard 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: 694-698Crossref PubMed Scopus (652) Google Scholar, 11Cleary S.P. Jeck W.R. Zhao X. et al.Identification of driver genes in hepatocellular carcinoma by exome sequencing.Hepatology. 2013; 58: 1693-1702Crossref PubMed Scopus (135) Google Scholar, 12Kan Z. Zheng H. Liu X. et al.Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma.Genome Res. 2013; 23: 1422-1433Crossref PubMed Scopus (230) Google Scholar, 13Ahn S.-M. Jang S.J. Shim J.H. et al.Genomic portrait of resectable hepatocellular carcinomas: implications of RB1 and FGF19 aberrations for patient stratification.Hepatology. 2014; 60: 1972-1982Crossref PubMed Scopus (128) Google Scholar, 14Jhunjhunwala S. Jiang Z. Stawiski E.W. et al.Diverse modes of genomic alteration in hepatocellular carcinoma.Genome Biol. 2014; 15: 436PubMed Google Scholar, 15Totoki Y. Tatsuno K. Covington K.R. et al.Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.Nat Genet. 2014; 46: 1267-1273Crossref PubMed Google Scholar, 16Shiraishi Y. Fujimoto A. Furuta M. et al.Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers.PLoS One. 2014; 9: e114263Crossref PubMed Scopus (28) Google Scholar, 17Schulze K. Imbeaud S. Letouzé E. et al.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet. 2015; 47: 505-511Crossref PubMed Scopus (375) Google Scholar, 18Fujimoto A. Furuta M. Totoki Y. et al.Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.Nat Genet. 2016; 48: 500-509Crossref PubMed Scopus (237) Google Scholar, 19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar The well-characterized mutations in HCCs are in CTNNB1 (which encodes β-catenin), TP53, AXIN1, RB1, ARID1A, ARID2, and NFE2L2. Mutations in the catalytic telomerase reverse transcriptase (TERT) have been more recently recognized as frequent driver events detected in 40%–65% of HCC samples.15Totoki Y. Tatsuno K. Covington K.R. et al.Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.Nat Genet. 2014; 46: 1267-1273Crossref PubMed Google Scholar, 17Schulze K. Imbeaud S. Letouzé E. et al.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet. 2015; 47: 505-511Crossref PubMed Scopus (375) Google Scholar, 19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 20Nault J.C. Mallet M. Pilati C. et al.High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.Nat Commun. 2013; 4: 2218Crossref PubMed Scopus (242) Google Scholar, 21Nault J.C. Calderaro J. Di Tommaso L. et al.Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis.Hepatology. 2014; 60: 1983-1992Crossref PubMed Scopus (102) Google Scholar The first case of germline mutation in TERT was initially discovered in an analysis of data from The Cancer Genome Atlas of HCC, implying germline mutations in TERT might cause inherited forms of HCC.19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar TERT promoter mutations cause overexpression of telomerase, which allows cells to become immortal. Mutations in the TERT promoter that increase its expression appear to be early events in hepatocarcinogenesis.20Nault J.C. Mallet M. Pilati C. et al.High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.Nat Commun. 2013; 4: 2218Crossref PubMed Scopus (242) Google Scholar, 21Nault J.C. Calderaro J. Di Tommaso L. et al.Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis.Hepatology. 2014; 60: 1983-1992Crossref PubMed Scopus (102) Google Scholar Furthermore, the TERT gene appears to be altered by HBV and HCV infection, via different mechanisms. Mutations in the TERT promoter have been more frequently associated with HCC resulting from chronic HCV infection and alcohol intake20Nault J.C. Mallet M. Pilati C. et al.High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.Nat Commun. 2013; 4: 2218Crossref PubMed Scopus (242) Google Scholar, 22Pezzuto F. Izzo F. Buonaguro L. et al.Tumor specific mutations in TERT promoter and CTNNB1 gene in hepatitis B and hepatitis C related hepatocellular carcinoma.Oncotarget. 2016; 7: 54253-54262Crossref PubMed Scopus (9) Google Scholar than with HBV-associated HCC. However, in HBV-related HCC, telomerase expression can be activated by recurrent integration of HBV into the TERT promoter.23Zhao L.-H. Liu X. Yan H.-X. et al.Genomic and oncogenic preference of HBV integration in hepatocellular carcinoma.Nat Commun. 2016; 7: 12992Crossref PubMed Scopus (30) Google Scholar TERT alterations promote cell immortality and transformation also via interactions with transcriptions factors, such as MYC,24Tang B. Xie R. Qin Y. et al.Human telomerase reverse transcriptase (hTERT) promotes gastric cancer invasion through cooperating with c-Myc to upregulate heparanase expression.Oncotarget. 2015; 7 (Available at:) (Accessed January 7, 2019): 11364-11379https://doi.org/10.18632/oncotarget.6575Google Scholar β-catenin,25Park J.-I. Venteicher A.S. Hong J.Y. et al.Telomerase modulates Wnt signalling by association with target gene chromatin.Nature. 2009; 460: 66-72Crossref PubMed Scopus (372) Google Scholar and NF-κB,26Ghosh A. Saginc G. Leow S.C. et al.Telomerase directly regulates NF-κB-dependent transcription.Nat Cell Biol. 2012; 14: 1270-1281Crossref PubMed Scopus (126) Google Scholar to alter expression of their target genes. Mutations that disrupt the function of TP53 are detected in 12%–48% of HCCs, and with high frequency in advanced tumors, but no therapeutic strategies have been developed to restore TP53 function to cells. An analysis of HCCs in The Cancer Genome Atlas identified a TP53-regulated gene expression signature that can be used to identify HCC tumors with loss of TP53 function—even when the TP53 gene is not mutated. The TP53-regulated gene expression signature was associated with clinical outcome and might be used as a biomarker to select treatment. HCCs have developed methods to reduce TP53 activity without mutating the TP53 gene. For example, TP53 levels are reduced in liver tissues from patients with chronic HBV infection via direct repression of the TP53 gene promoter by HBx.27Lee S.G. Rho H.M. Transcriptional repression of the human p53 gene by hepatitis B viral X protein.Oncogene. 2000; 19: 468-471Crossref PubMed Google Scholar Activating mutations of in CTNNB1 have been found in 11%–37% of HCC samples, and inactivating mutations in AXIN1 have been found in 5%–15% of HCCs. These mutations activate Wnt signaling, which promotes cell motility, de-differentiation, and proliferation.28Wong C.M. Fan S.T. Ng I.O. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance.Cancer. 2001; 92: 136-145Crossref PubMed Scopus (283) Google Scholar Mutations in proteins that regulate chromatin remodeling, such as ARID1A, are detected in 4%–17% of HCCs; ARID2 mutations are found in 3%–18% of HCCs.9Fujimoto A. Totoki Y. Abe T. et al.Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators.Nat Genet. 2012; 44: 760-764Crossref PubMed Scopus (472) Google Scholar, 14Jhunjhunwala S. Jiang Z. Stawiski E.W. et al.Diverse modes of genomic alteration in hepatocellular carcinoma.Genome Biol. 2014; 15: 436PubMed Google Scholar, 19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar These mutations lead to transcriptional repression of genes regulated by the transcription factor E2F. In normal cells, these genes block cell proliferation by upregulating CDKN1A, which encodes the cyclin-dependent kinase inhibitor P21.29Guo X.-Q. Zhang Q.-X. Huang W.-R. et al.[Tumor suppressor role of chromatin-remodeling factor ARID1A].Yi Chuan. 2013; 35: 255-261Crossref PubMed Scopus (1) Google Scholar Many HCC cells contain copy number alterations that result in either gains or losses of segments of genomic DNA. Genes with increased copy numbers amplifications in HCC include FGF19 and CCND1. Amplification of FGF19 results in increased expression of its product and FGF pathway activation.17Schulze K. Imbeaud S. Letouzé E. et al.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet. 2015; 47: 505-511Crossref PubMed Scopus (375) Google Scholar, 30Sawey E.T. Chanrion M. Cai C. et al.Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening.Cancer Cell. 2011; 19: 347-358Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar Brivanib, an inhibitor of VEGF and FGF, did not provide clinical benefit to patients with HCC. However, lenvatinib, another inhibitor of multiple tyrosine kinase receptors, including FGF receptors, increased survival times in patients with HCC in a phase 3 trial.31Johnson P.J. Qin S. Park J.-W. et al.Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.J Clin Oncol. 2013; 31: 3517-3524Crossref PubMed Google Scholar, 32Kudo M. Finn R.S. Qin S. et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet. 2018; 391: 1163-1173Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Other highly potent or irreversible FGFR inhibitors are being evaluated in patients and these might be more effective and have better safety profiles.33Kim R. Sharma S. Meyer T. et al.First-in-human study of BLU-554, a potent, highly-selective FGFR4 inhibitor designed for hepatocellular carcinoma (HCC) with FGFR4 pathway activation.Eur J Cancer. 2016; 69: S41Abstract Full Text PDF Google Scholar Other oncogenes that are frequently amplified in HCCs include TERT, VEGFA, MYC, CCND1, and MET,10Guichard 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: 694-698Crossref PubMed Scopus (652) Google Scholar, 14Jhunjhunwala S. Jiang Z. Stawiski E.W. et al.Diverse modes of genomic alteration in hepatocellular carcinoma.Genome Biol. 2014; 15: 436PubMed Google Scholar, 19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar whereas tumor suppressor genes, such as PTEN34Xu Z. Hu J. Cao H. et al.Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway.Exp Mol Med. 2018; 50: e417Crossref PubMed Google Scholar, 35Wang L. Wang W.-L. Zhang Y. et al.Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma.Hepatol Res. 2007; 37: 389-396Crossref PubMed Scopus (0) Google Scholar and CDKN2A (encoding P16INK4A), are frequently deleted in HCC samples.36Biden K. Young J. Buttenshaw R. et al.Frequency of mutation and deletion of the tumor suppressor gene CDKN2A (MTS1/p16) in hepatocellular carcinoma from an Australian population.Hepatology. 1997; 25: 593-597Crossref PubMed Scopus (0) Google Scholar, 37Jin M. Piao Z. Kim N.G. et al.p16 is a major inactivation target in hepatocellular carcinoma.Cancer. 2000; 89: 60-68Crossref PubMed Scopus (0) Google Scholar Loss of these genes leads to cell cycle progression and proliferation. Epigenetic alterations also alter gene expression to affect cell and tissue phenotypes.38Jones P.A. Baylin S.B. The epigenomics of cancer.Cell. 2007; 128: 683-692Abstract Full Text Full Text PDF PubMed Scopus (2948) Google Scholar Epigenetic modifications occur via processes, such as DNA methylation, covalent modifications to chromatin, alterations in nucleosome position, and changes in levels of microRNAs and lncRNAs. Epigenetic and genetic events can cooperate to promote tumorigenesis or progression and metastasis. For example, TERT promoter mutations frequently co-occur with silencing of CDKN2A by promoter hypermethylation.19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar The combination of telomerase overexpression and silencing of a cell-cycle checkpoint inhibitor contribute to cell immortalization.39Kiyono T. Foster S.A. Koop J.I. et al.Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells.Nature. 1998; 396: 84-88Crossref PubMed Scopus (1011) Google Scholar Some genes that are silenced by promoter hypermethylation during hepatocarcinogenesis include the suppressor of cytokine signaling 1 (SOCS1),40Zhang C. Guo X. Jiang G. et al.CpG island methylator phenotype association with upregulated telomerase activity in hepatocellular carcinoma.Int J Cancer. 2008; 123: 998-1004Crossref PubMed Scopus (0) Google Scholar, 41Zhang X. Wang J. Cheng J. et al.An integrated analysis of SOCS1 down-regulation in HBV infection-related hepatocellular carcinoma.J Viral Hepat. 2014; 21: 264-271Crossref PubMed Scopus (10) Google Scholar hedgehog interacting protein (HHIP),19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 42Tada M. Kanai F. Tanaka Y. et al.Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma.Clin Cancer Res. 2008; 14: 3768-3776Crossref PubMed Scopus (64) Google Scholar CDKN2A, CDKN1A, CDKN2B,43Wahid B. Ali A. Rafique S. et al.New insights into the epigenetics of hepatocellular carcinoma.Biomed Res Int. 2017; 2017: 1609575Crossref PubMed Scopus (20) Google Scholar APC,44Csepregi A. Röcken C. Hoffmann J. et al.APC promoter methylation and protein expression in hepatocellular carcinoma.J Cancer Res Clin Oncol. 2008; 134: 579-589Crossref PubMed Scopus (0) Google Scholar carbamoyl-phosphate synthase 1 (CPS1, a urea cycle gene),45Liu H. Dong H. Robertson K. et al.DNA methylation suppresses expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) in human hepatocellular carcinoma.Am J Pathol. 2011; 178: 652-661Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar TIMP metallopeptidase inhibitor 3 (TIMP3),46Defamie V. Sanchez O. Murthy A. et al.TIMP3 controls cell fate to confer hepatocellular carcinoma resistance.Oncogene. 2015; 34: 4098-4108Crossref PubMed Scopus (10) Google Scholar and glutathione S-transferase pi 1 (GSTP1).47Zhang Y.-J. Chen Y. Ahsan H. et al.Silencing of glutathione S-transferase P1 by promoter hypermethylation and its relationship to environmental chemical carcinogens in hepatocellular carcinoma.Cancer Lett. 2005; 221: 135-143Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar HCV and HBV can induce epigenetic modifications that promote liver tumorigenesis. HCV induces overexpression of protein phosphatase 2 catalytic subunit α (PPP2CA), leading to deregulation of histone modifications, altered gene expression, and anchorage-independent growth.48Duong F.H.T. Christen V. Lin S. et al.Hepatitis C virus-induced up-regulation of protein phosphatase 2A inhibits histone modification and DNA damage repair.Hepatology. 2010; 51: 741-751PubMed Google Scholar In vivo and in vitro studies have shown that HCV can induce promoter hypermethylation and silencing of GADD45B, leading to aberrant cell-cycle arrest and diminished DNA excision repair.49Higgs M.R. Lerat H. Pawlotsky J.-M. Downregulation of Gadd45beta expression by hepatitis C virus leads to defective cell cycle arrest.Cancer Res. 2010; 70: 4901-4911Crossref PubMed Scopus (0) Google Scholar HBV infection also appears to lead to unique DNA methylation patterns that suppress genes, including MDM2, FGF4, FGF19, and HSP90AA1.50Ye C. Tao R. Cao Q. et al.Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma.Int J Oncol. 2016; 49: 589-602Crossref PubMed Scopus (3) Google Scholar HBV alters the epigenome via HBx protein.51Park I.Y. Sohn B.H. Yu E. et al.Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein.Gastroenterology. 2007; 132: 1476-1494Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 52Tian Y. Yang W. Song J. et al.Hepatitis B virus X protein-induced aberrant epigenetic modifications contributing to human hepatocellular carcinoma pathogenesis.Mol Cell Biol. 2013; 33: 2810-2816Crossref PubMed Scopus (73) Google Scholar HBx increases total DNA methyltransferase activity and promotes regional hypermethylation of specific tumor suppressor genes.51Park I.Y. Sohn B.H. Yu E. et al.Aberrant epigenetic modifications in hepatocarcinogenesis induced by hepatitis B virus X protein.Gastroenterology. 2007; 132: 1476-1494Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 53Zheng D.-L. Zhang L. Cheng N. et al.Epigenetic modification induced by hepatitis B virus X protein via interaction with de novo DNA methyltransferase DNMT3A.J Hepatol. 2009; 50: 377-387Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar HBx also promotes recruitment and transactivation of co-activators of the CREB-binding protein CBP–P300 complex, leading to acetylation and thereby activation of cellular genes.54Cougot D. Wu Y. Cairo S. et al.The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.J Biol Chem. 2007; 282: 4277-4287Crossref PubMed Scopus (0) Google Scholar MicroRNAs are short (20–22 nucleotide) non-coding RNAs that pair with complementary 3'-untranslated regions messenger RNAs, inhibiting their translation or leading to their degradation.55Macfarlane L.-A. Murphy P.R. MicroRNA: biogenesis, function and role in cancer.Curr Genomics. 2010; 11: 537-561Crossref PubMed Google Scholar A single microRNA can control levels of several messenger RNAs to regulate biological processes, such apoptosis, differentiation, and metastasis. One of the most abundant microRNAs in the liver is microRNA 122 (MIR122), which is involved in regulating several genes in the cholesterol metabolism pathway and is also required for HCV replication.56Bandiera S. Pfeffer S. Baumert T.F. et al.miR-122–A key factor and therapeutic target in liver disease.J Hepatol. 2015; 62: 448-457Abstract Full Text Full Text PDF PubMed Google Scholar Levels of MIR122 are significantly reduced in HCCs,19Cancer Genome Atlas Research NetworkComprehensive and integrative genomic characterization of hepatocellular carcinoma.Cell. 2017; 169: 1327-1341.e23Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 57Kishikawa T. Otsuka M. Tan P.S. et al.Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine.Oncotarget. 2015; 6: 8339-8352Crossref PubMed Scopus (11) Google Scholar which is associated with metastasis and poor outcomes. MIR122-knockout mice develop spontaneous liver tumors resembling HCCs58Hsu S.-H. Wang B. Kota J. et al.Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver.J Clin Invest. 2012; 122: 2871-2883Crossref PubMed Scopus (403) Google Scholar and re-expression of MIR122 reduced tumor incidence and development in Mir122a–/– mice.58Hsu S.-H. Wang B. Kota J. et al.Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver.J Clin Invest. 2012; 122: 2871-2883Crossref PubMed Scopus (403) Google Scholar, 59Tsai W.-C. Hsu S.-D. Hsu C.-S. et al.MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis.J Clin Invest. 2012; 122: 2884-2897Crossref PubMed Scopus (458) Google Scholar MIR375 is also downregulated in HCCs and appears to function as a tumor suppressor. Delivery of MIR375 into HCC cells, via MIR375 mimics on the surface of gold nanoparticles, reduced proliferation, and induced apoptosis.60Xue H.-Y. Liu Y. Liao J.-Z. et al.Gold nanoparticles delivered miR-375 for treatment of hepatocellular carcinoma.Oncotarget. 2016; 7: 86675-86686Crossref PubMed Scopus (11) Google Scholar Several microRNAs appear to promote tumorigenesis, called oncomirs. Their levels are increased expression HCCs. MIR221 is one of the most highly expressed microRNAs in HCCs; transgenic expression in mice leads to liver tumor development.61Callegari E. Elamin B.K. Giannone F. et al.Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model.Hepatology. 2012; 56: 1025-1033Crossref PubMed Scopus (96) Google Scholar Inhibition of MIR221 with an anti-sense oligonucleotide delayed tumor growth in Mir221 transgenic mice.61Callegari E. Elamin B.K. Giannone F. et al.Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model.Hepatology. 2012; 56: 1025-1033Crossref PubMed Scopus (96) Google Scholar The MIR17–92 cluster encodes at least 6 microRNAs that regulate cell survival, proliferation, differentiation, and angiogenesis. MIR17–92 is significantly overexpressed in HCCs, and its liver-specific overexpression promoted tumor development in transgenic mice.62Zhu H. Han C. Wu T. MiR-17-92 cluster promotes hepatocarcinogenesis.Carcinogenesis. 2015; 36: 1213-1222Crossref PubMed Scopus (32) Google Scholar Delivery of anti-MIR17 oligonucleotide via lipid nanoparticles was able to delay MYC-induced tumorigenesis in mice.63Dhanasekaran R. Gabay-Ryan M. Baylot V. et al.Anti-miR-17 therapy delays tumorigenesis in MYC-driven hepatocellular carcinoma (HCC).Oncotarget. 2018; 9: 5517-5528Crossref PubMed Scopus (1) Google Scholar MicroRNAs might therefore serve as therapeutic targets and also as serum biomarkers. In a nested case–control study performed in China, expression patterns of 7 microRNAs (MIR29a, MIR29c, MIR133a, MIR143, MIR145, MIR192, and MIR505) could be used to identify patients with early-stage HCC.64Lin X.-J. Chong Y. Guo Z.-W. et al.A serum microRNA classifier for early
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