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• W2945017572 abstract "Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development. Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development. Key points•Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate•Initial data suggest that HDV accelerates the progression to cirrhosis and increases the risk of hepatocellular carcinoma (HCC) in patients with HBV•Proposed mechanisms for HDV enhance HBV-related oncogenesis include activation of pathways related to inflammation and fibrosis•Unlike HBV, there is limited data to support a direct oncogenic role of HDV in human hepatocarcinogenesis •Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate•Initial data suggest that HDV accelerates the progression to cirrhosis and increases the risk of hepatocellular carcinoma (HCC) in patients with HBV•Proposed mechanisms for HDV enhance HBV-related oncogenesis include activation of pathways related to inflammation and fibrosis•Unlike HBV, there is limited data to support a direct oncogenic role of HDV in human hepatocarcinogenesis More than 40 years after its discovery,[1]Rizzetto M Canese MG Arico S et al.Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers.Gut. 1977; 18: 997-1003https://doi.org/10.1136/gut.18.12.997Crossref PubMed Scopus (686) Google Scholar key features of hepatitis delta virus (HDV) infection remain unknown. This contrasts with other hepatotropic viruses, such as hepatitis B (HBV) and hepatitis C virus (HCV), which have been thoroughly investigated and for which there are effective treatments. The lower prevalence of HDV compared to HBV or HCV likely justified the limited research efforts dedicated to HDV, even though HDV infection is highly prevalent in certain countries.[2]Lempp FA Ni Y Urban S Hepatitis delta virus: Insights into a peculiar pathogen and novel treatment options.Nat Rev Gastroenterol Hepatol. 2016; 13: 580-589https://doi.org/10.1038/nrgastro.2016.126Crossref PubMed Scopus (104) Google Scholar HDV is a defective virus that co-exists with HBV, and is related to the most severe form of liver failure attributable to chronic viral hepatitis. HDV is understood to accelerate the progression to cirrhosis, and it is considered a main driver of the malignant hepatocyte transformation.[3]Wedemeyer H Manns MP Epidemiology, pathogenesis and management of hepatitis D: Update and challenges ahead.Nat Rev Gastroenterol Hepatol. 2010; 7: 31-40https://doi.org/10.1038/nrgastro.2009.205Crossref PubMed Scopus (285) Google Scholar HBV/HDV-coinfected patients seem to be at an increased risk of HCC development compared to HBV-monoinfected individuals, although the evidence is still limited. Thus, HDV is not yet included on the list of oncogenic agents, whilst HBV and HCV are well defined carcinogens.[4]https://monographs.iarc.fr/agents-classified-by-the-iarcDate: 2018Google Scholar Herein, we will review the evidence available regarding the oncogenic role and mechanisms of HDV-related carcinogenesis, as well as discussing the key unmet needs in HDV research. The global prevalence of HDV is remarkably variable (Fig. 1).[5]Hughes SA Wedemeyer H Harrison PM Hepatitis delta virus.Lancet. 2011; 378: 73-85https://doi.org/10.1016/S0140-6736(10)61931-9Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar As routine testing for HDV in HBV surface antigen (HBsAg)-positive individuals is not a standard procedure,[6]Terrault NA Lok ASF McMahon BJ et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599https://doi.org/10.1002/hep.29800Crossref PubMed Scopus (1811) Google Scholar HDV prevalence is unknown in many countries, resulting in a global underestimation of HDV disease burden. To date, few studies have evaluated the global burden of HDV, and available data are mostly biased towards local reports from different regions in specific cohorts. The World Health Organization (WHO) estimates that there are at least 20 million people infected with HDV worldwide, which represents 5% of HBV carriers.[7]World Health Organization Global Hepatitis Report, 2017.2017Google Scholar A recent meta-analysis including 182 articles from 61 countries estimated a pooled HDV prevalence of 10%, even after excluding intravenous drug users and individuals with high-risk sexual behaviour.[8]Chen H-Y Shen D-T Ji D-Z et al.Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.Gut. September 2018; https://doi.org/10.1136/gutjnl-2018-316601Crossref Scopus (161) Google Scholar However, methodological errors regarding the definition of HDV infection, extrapolation of data from the different cohorts, and selection bias have been pointed out in this study. Thus, it is likely that such analysis represents an overestimation of the real prevalence.[9]Stockdale AJ Kreuels B Henrion MR Giorgi E Kyomuhangi I Geretti AM Hepatitis D prevalence: problems with extrapolation to global population estimates.Gut. 2019; (Epub ahead)https://doi.org/10.1136/gutjnl-2018-317874Crossref Scopus (24) Google Scholar In certain areas such as Nigeria, Gabon, Benin, Mauritania, Cameroon, Senegal, Iran, Peru, the Western Brazilian Amazon, the mountain regions of Colombia and Venezuela, Romania, Pakistan, and Tajikistan, the reported HDV prevalence exceeds 20%.2Lempp FA Ni Y Urban S Hepatitis delta virus: Insights into a peculiar pathogen and novel treatment options.Nat Rev Gastroenterol Hepatol. 2016; 13: 580-589https://doi.org/10.1038/nrgastro.2016.126Crossref PubMed Scopus (104) Google Scholar, 5Hughes SA Wedemeyer H Harrison PM Hepatitis delta virus.Lancet. 2011; 378: 73-85https://doi.org/10.1016/S0140-6736(10)61931-9Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar, 10Stockdale AJ Chaponda M Beloukas A et al.Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e992-e1003https://doi.org/10.1016/S2214-109X(17)30298-XAbstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 11Scarponi CFO Silva RDND Souza Filho JA Guerra MRL Pedrosa MAF Mol MPG Hepatitis Delta Prevalence in South America: A Systematic Review and Meta-Analysis.Rev Soc Bras Med Trop. 2019; 52e20180289https://doi.org/10.1590/0037-8682-0289-2018Crossref PubMed Scopus (20) Google Scholar HDV is endemic in Punjab, Somalia, and Mongolia, with an estimated prevalence of up to 60–80% in HBV-infected patients.12Rizzetto M The adventure of delta.Liver Int. 2016; 36: 135-140https://doi.org/10.1111/liv.13018Crossref PubMed Scopus (48) Google Scholar, 13Chen X Oidovsambuu O Liu P et al.A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus-infected mongolians.Hepatology. 2017; 66: 1739-1749https://doi.org/10.1002/hep.28957Crossref PubMed Scopus (54) Google Scholar Remarkably, these estimates of prevalence may be biased, as they are usually extrapolated from high-risk cohorts. HDV prevalence also varies across risk factors, with prevalences of 37% and 17% in intravenous drug users and people with high-risk sexual behaviours, respectively.[8]Chen H-Y Shen D-T Ji D-Z et al.Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.Gut. September 2018; https://doi.org/10.1136/gutjnl-2018-316601Crossref Scopus (161) Google Scholar Eight different HDV genotypes have been identified,14Dény P Hepatitis delta virus genetic variability: from genotypes I, II, III to eight major clades?.Curr Top Microbiol Immunol. 2006; 307: 151-171http://www.ncbi.nlm.nih.gov/pubmed/16903225Crossref PubMed Scopus (111) Google Scholar, 15Le Gal F Brichler S Drugan T et al.Genetic diversity and worldwide distribution of the deltavirus genus: A study of 2,152 clinical strains.Hepatology. 2017; 66: 1826-1841https://doi.org/10.1002/hep.29574Crossref PubMed Scopus (69) Google Scholar with data suggesting different disease courses depending on genotype.[16]Sureau C Negro F The hepatitis delta virus: Replication and pathogenesis.J Hepatol. 2016; 64: S102-S116https://doi.org/10.1016/j.jhep.2016.02.013Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar Genotype 1, the most common, has worldwide distribution but is predominant in Europe, the Mediterranean countries, Iran, Turkey, and North America. Genotypes 2 and 4 are found in Asia, genotype 3 has only been described in South America, and genotypes 5-8 are found almost exclusively in Africa.[17]Rizzetto M Ciancio A Epidemiology of hepatitis D.Semin Liver Dis. 2012; 32: 211-219https://doi.org/10.1055/s-0032-1323626Crossref PubMed Scopus (81) Google Scholar Genotype 1 has been associated with worse outcomes than genotype 2, including progression to cirrhosis and higher rates of HCC.18Wu JC Choo KB Chen CM Chen TZ Huo TI Lee SD Genotyping of hepatitis D virus by restriction-fragment length polymorphism and relation to outcome of hepatitis D.Lancet (London, England). 1995; 346: 939-941http://www.ncbi.nlm.nih.gov/pubmed/7564729Abstract PubMed Scopus (122) Google Scholar, 19Su C Huang Y Huo T et al.Genotypes and Viremia of Hepatitis B and D Viruses Are Associated With Outcomes of Chronic Hepatitis D Patients.Gastroenterology. 2006; 130: 1625-1635https://doi.org/10.1053/j.gastro.2006.01.035Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar HDV is a circular single-stranded negative-sense RNA virus which encodes for a single protein, the delta protein or delta antigen (HDAg).[5]Hughes SA Wedemeyer H Harrison PM Hepatitis delta virus.Lancet. 2011; 378: 73-85https://doi.org/10.1016/S0140-6736(10)61931-9Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar The delta antigen was discovered in Italy in 1977 by Rizzetto and collaborators while examining liver biopsies of chronic HBV patients with direct immunofluorescence. They noticed that some HBV-infected patients reacted and revealed a nuclear fluorescent pattern, which was initially thought to be a new HBV antigen.[1]Rizzetto M Canese MG Arico S et al.Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers.Gut. 1977; 18: 997-1003https://doi.org/10.1136/gut.18.12.997Crossref PubMed Scopus (686) Google Scholar It was not until 1980 when they realised that it was a new RNA virus.[20]Rizzetto M Hoyer B Canese MG Shih JW Purcell RH Gerin JL. delta Agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees.Proc Natl Acad Sci U S A. 1980; 77: 6124-6128http://www.ncbi.nlm.nih.gov/pubmed/6934539Crossref PubMed Scopus (349) Google Scholar The HDV genome spams between 1,672 and 1,697 base pairs depending on the genotype, making it the smallest virus infecting humans. HDV shares more characteristics with plant virusoids than with other human pathogens, such as the circular configuration of its RNA genome, its RNA self-cleavage (ribozyme activity) property and its RNA to RNA rolling circle replication. 21Ciancio A Rizzetto M Chronic hepatitis D at a standstill: Where do we go from here?.Nat Rev Gastroenterol Hepatol. 2014; 11: 68-71https://doi.org/10.1038/nrgastro.2013.164Crossref PubMed Scopus (38) Google Scholar, 22Yurdaydın C Idilman R Bozkaya H Bozdayi AM Natural history and treatment of chronic delta hepatitis.J Viral Hepat. 2010; 17: 749-756https://doi.org/10.1111/j.1365-2893.2010.01353.xCrossref PubMed Scopus (116) Google Scholar HDV is a defective virus which needs the presence of HBV for infectivity and assembly purposes, as it lacks its own envelope and uses HBsAg instead.[1]Rizzetto M Canese MG Arico S et al.Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers.Gut. 1977; 18: 997-1003https://doi.org/10.1136/gut.18.12.997Crossref PubMed Scopus (686) Google Scholar The preS1 domain of the large HBsAg (L-HBsAg) is necessary to infect hepatocytes by binding to the sodium taurocholate cotransporting polypeptide (NTCP) receptor, and the small HBsAg (S-HBsAg) is essential for HDV assembly. Notably, HDV does not need active HBV DNA synthesis, which is inhibited in patients under effective anti-HBV treatment with nucleos(t)ide analogues (NUCs). HDV is able to replicate as long as the translation of these structural proteins continues. Furthermore, integrated HBV DNA can also provide the necessary envelope proteins for HDV virions, independently of HBV replication.23Botelho-Souza LF Vasconcelos MPA Dos Santos ADO Salcedo JMV Vieira DS Hepatitis delta: Virological and clinical aspects.Virol J. 2017; 14: 1-15https://doi.org/10.1186/s12985-017-0845-yCrossref PubMed Scopus (52) Google Scholar, 24Freitas N Cunha C Menne S Gudima SO Envelope proteins derived from naturally integrated hepatitis B virus DNA support assembly and release of infectious hepatitis delta virus particles.J Virol. 2014; 88: 5742-5754https://doi.org/10.1128/JVI.00430-14Crossref PubMed Scopus (55) Google Scholar In addition to its dependence on HBV, HDV replication also needs a host (i.e. the hepatocyte), as the virus does not code for an RNA polymerase but uses the host’s machinery.[2]Lempp FA Ni Y Urban S Hepatitis delta virus: Insights into a peculiar pathogen and novel treatment options.Nat Rev Gastroenterol Hepatol. 2016; 13: 580-589https://doi.org/10.1038/nrgastro.2016.126Crossref PubMed Scopus (104) Google Scholar The delta protein is expressed in 2 isoforms with complementary functions: the small form, called S-HDAg or p24 for its molecular weight of 24 kDa, regulates the nuclear import of HDV ribonucleoproteins and the replication process. The large form, called L-HDAg or p27, inhibits replication and participates in virion assembly.[25]Taylor JM Hepatitis delta virus.Virology. 2006; 344: 71-76https://doi.org/10.1016/j.virol.2005.09.033Crossref PubMed Scopus (171) Google Scholar During HDV replication, HDAg proteins form a ribonucleoprotein, which will later get a coat in the endoplasmic reticulum consisting of the 3 HBV HBsAg proteins.[16]Sureau C Negro F The hepatitis delta virus: Replication and pathogenesis.J Hepatol. 2016; 64: S102-S116https://doi.org/10.1016/j.jhep.2016.02.013Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar Thus, the outer envelope is the same for HBV and HDV, which has crucial implications in the interaction between the 2 viruses.[26]Giersch K Dandri M Hepatitis B and Delta Virus: Advances on Studies about Interactions between the Two Viruses and the Infected Hepatocyte.J Clin Transl Hepatol. 2015; 3: 220-229https://doi.org/10.14218/JCTH.2015.00018Crossref PubMed Scopus (27) Google Scholar There is no data on the molecular alterations present in patients with HDV-related HCC. This is particularly unfortunate for studies on genome-wide mutation profiling, which could identify druggable mutations particularly enriched in these patients. HDV does not integrate into the genome and lacks the machinery required to propagate in the absence of HBV. Thus, a direct oncogenic mechanism of HDV is unlikely. However, the interactions between HDV and HBV could also help promote HCC development.[27]Romeo R Petruzziello A Pecheur EI et al.Epidemiology and Infection Hepatitis delta virus and hepatocellular carcinoma: an update.2018https://doi.org/10.1017/S0950268818001942Crossref Scopus (26) Google Scholar Preliminary data have indicated potential mechanisms by which HDV can modify key signalling pathways related to fibrosis, including epigenetic changes, immune response modifications, specific dysregulation of long non-coding RNAs (lncRNAs), and proteomic changes (Fig. 2). Enhanced transforming growth factor-β (TGF-β) signalling has been proposed as a mechanism behind the accelerated liver disease in HBV/HDV-coinfected patients. TGF-β is involved in multiple cellular processes, including growth, differentiation, wound repair and apoptosis, with a major regulatory role in fibrosis and hepatocarcinogenesis.[28]Majumdar A Curley SA Wu X et al.Hepatic stem cells and transforming growth factor β in hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol. 2012; 9: 530-538https://doi.org/10.1038/nrgastro.2012.114Crossref PubMed Scopus (119) Google Scholar L-HDAg can activate the TGF-β pathway, probably via the Smad3 protein, which could promote HCC development.[29]Choi SH Jeong SH Hwang SB Large Hepatitis Delta Antigen Modulates Transforming Growth Factor-β Signaling Cascades: Implication of Hepatitis Delta Virus-Induced Liver Fibrosis.Gastroenterology. 2007; 132: 343-357https://doi.org/10.1053/j.gastro.2006.10.038Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Since HBV can also upregulate TGF-β via the HBx protein,[30]Levrero M Zucman-Rossi J Mechanisms of HBV-induced hepatocellular carcinoma.J Hepatol. 2016; 64: S84-S101https://doi.org/10.1016/j.jhep.2016.02.021Abstract Full Text Full Text PDF PubMed Scopus (530) Google Scholar this could be a mechanism by which HDV enhances HBV-related oncogenesis. L-HDAg has been shown to activate c-Jun and to antagonize the inhibitory effect of c-Jun over TGF-β.[29]Choi SH Jeong SH Hwang SB Large Hepatitis Delta Antigen Modulates Transforming Growth Factor-β Signaling Cascades: Implication of Hepatitis Delta Virus-Induced Liver Fibrosis.Gastroenterology. 2007; 132: 343-357https://doi.org/10.1053/j.gastro.2006.10.038Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar This effect could be synergistic with that of the HBx protein, which also activates these 2 signalling cascades.[31]Murata M Matsuzaki K Yoshida K et al.Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B.Hepatology. 2009; 49: 1203-1217https://doi.org/10.1002/hep.22765Crossref PubMed Scopus (144) Google Scholar Another proposed mechanism involves nuclear factor kappa B (NF-κB), a transcription factor with crucial roles in inflammation, immunity, cell proliferation and apoptosis, and HCC development.[32]Luedde T Schwabe RF NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma.Nat Rev Gastroenterol Hepatol. 2011; 8: 108-118https://doi.org/10.1038/nrgastro.2010.213Crossref PubMed Scopus (885) Google Scholar L-HDAg can induce NF-κB activation via tumor necrosis factor-α (TNF-α) stimulation[33]Park CY Oh SH Kang SM Lim YS Hwang SB Hepatitis delta virus large antigen sensitizes to TNF-α-induced NF-κB signaling.Mol Cells. 2009; 28: 49-55https://doi.org/10.1007/s10059-009-0100-5Crossref PubMed Scopus (27) Google Scholar or oxidative stress.[34]Williams V Brichler S Khan E et al.Large hepatitis delta antigen activates STAT-3 and NF-κB via oxidative stress.J Viral Hepat. 2012; 19: 744-753https://doi.org/10.1111/j.1365-2893.2012.01597.xCrossref PubMed Scopus (40) Google Scholar L-HDAg has also been related to the activation of other known oncogenic pathways including the JAK-STAT pathway[35]He G Karin M NF-κB and STAT3 - key players in liver inflammation and cancer.Cell Res. 2011; 21: 159-168https://doi.org/10.1038/cr.2010.183Crossref PubMed Scopus (841) Google Scholar (via activation of the signal transducer and activator of transcription 3 [STAT-3] downstream protein[34]Williams V Brichler S Khan E et al.Large hepatitis delta antigen activates STAT-3 and NF-κB via oxidative stress.J Viral Hepat. 2012; 19: 744-753https://doi.org/10.1111/j.1365-2893.2012.01597.xCrossref PubMed Scopus (40) Google Scholar) or c-Fos activation.[36]Goto T Kato N Ono-Nita SK et al.Large isoform of hepatitis delta antigen activates serum response factor-associated transcription.J Biol Chem. 2000; 275: 37311-37316https://doi.org/10.1074/jbc.M002947200Crossref PubMed Scopus (26) Google Scholar Another reported mechanism for HDV-related oncogenesis is downregulation of glutathione S-transferase P1 (GSTP1), a tumour suppressor gene. Transfection with S-HDAg in fetal hepatic cell lines inhibited GSTP1 expression specifically by binding to its mRNA, which resulted in accumulation of reactive oxygen species and increased apoptosis.[37]Chen M Du D Zheng W et al.Small Hepatitis Delta Antigen Selectively Binds to Target mRNA in Hepatic Cells: A Potential Mechanism by Which Hepatitis D Virus Down-Regulates Glutathione S-Transferase P1 and Induces Liver Injury and Hepatocarcinogenesis.Biochem Cell Biol. August 2018; https://doi.org/10.1139/bcb-2017-0321Crossref Scopus (11) Google Scholar Inactivation of tumour suppressor genes through aberrant DNA methylation is frequent in HCC.[38]Villanueva A Portela A Sayols S et al.DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma.Hepatology. 2015; 61: 1945-1956https://doi.org/10.1002/hep.27732Crossref PubMed Scopus (253) Google Scholar Some studies have evaluated the capacity of HDV to interfere with DNA methylation. For example, the chaperon protein clusterin, which is involved in cell death regulation and frequently overexpressed in HCC,[39]Kang YK Hong SW Lee H Kim WH Overexpression of clusterin in human hepatocellular carcinoma.Hum Pathol. 2004; 35: 1340-1346https://doi.org/10.1016/j.humpath.2004.07.021Crossref PubMed Scopus (86) Google Scholar was found upregulated through histone acetylation in HDV-infected cell lines.[40]Liao FT Lee YJ Ko JL Tsai CC Tseng CJ Sheu GT Hepatitis delta virus epigenetically enhances clusterin expression via histone acetylation in human hepatocellular carcinoma cells.J Gen Virol. 2009; 90: 1124-1134https://doi.org/10.1099/vir.0.007211-0Crossref PubMed Scopus (37) Google Scholar Also, a small study in an HCC cell line overexpressing HDV found a mild increase in the levels of methyltransferase 3b.[41]Benegiamo G Vinciguerra M Guarnieri V Niro G Andriulli A Pazienza V Hepatitis delta virus induces specific DNA methylation processes in Huh-7 liver cancer cells.FEBS Lett. 2013; 587: 1424-1428https://doi.org/10.1016/j.febslet.2013.03.021Crossref PubMed Scopus (25) Google Scholar Other potential epigenetic mechanisms involved long non-coding RNAs (lncRNAs), including the deregulation of Y3 in HDV-related HCC.[42]Zhang Q Matsuura K Kleiner DE Zamboni F Alter HJ Farci P Analysis of long noncoding RNA expression in hepatocellular carcinoma of different viral etiology.J Transl Med. 2016; 14: 1-11https://doi.org/10.1186/s12967-016-1085-4Crossref PubMed Scopus (48) Google Scholar Notably, dysregulation of lncRNAs is crucial in HDV replication.[43]Beeharry Y Goodrum G Imperiale CJ Pelchat M The Hepatitis Delta Virus accumulation requires paraspeckle components and affects NEAT1 level and PSP1 localization.Sci Rep. 2018; 8: 1-12https://doi.org/10.1038/s41598-018-24500-1Crossref PubMed Scopus (18) Google Scholar In terms of immune dysregulation, there is data on humanised mice showing a higher number of interferon stimulated genes (ISGs) and cytokines such as TGF-β and interleukin-28 in HBV/HDV-coinfected human hepatocytes compared to HBV-monoinfected hepatocytes, suggesting enhanced inflammation in HDV.[44]Giersch K Allweiss L Volz T et al.Hepatitis Delta coinfection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV monoinfection.J Hepatol. 2015; 63: 346-353https://doi.org/10.1016/j.jhep.2015.03.011Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Finally, changes in the cellular proteome have also been linked to HDV infection, including differential expression of 89 proteins, predominantly affecting DNA damage checkpoints and the cell cycle.[45]Mendes M Pérez-Hernandez D Vázquez J Coelho AV Cunha C Proteomic changes in HEK-293 cells induced by hepatitis delta virus replication.J Proteomics. 2013; 89: 24-38https://doi.org/10.1016/j.jprot.2013.06.002Crossref PubMed Scopus (18) Google Scholar Most of this information comes from small studies, so a thorough evaluation of the key molecular features of HDV-related HCC is eagerly awaited. HBV is invariably present in all HDV-infected patients. The interaction between these 2 viruses is not completely understood but it seems to be reciprocal, and it may be crucial to the events that lead to disease progression. Intriguingly, HDV may persist for several months after liver transplantation without evidence of HBV replication.[46]Mederacke I Filmann N Yurdaydin C et al.Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis delta antigen persistence after liver transplantation.J Hepatol. 2012; 56: 115-122https://doi.org/10.1016/j.jhep.2011.06.016Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Besides, it has recently been shown that HDV replication may persist even in the absence of HBV.[47]Giersch K Bhadra OD Volz T et al.Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo.Gut. 2019; 68: 150-157https://doi.org/10.1136/gutjnl-2017-314713Crossref PubMed Scopus (47) Google Scholar Two types of infection can be distinguished. The acquisition of both viruses at the same time (i.e. coinfection) is an important cause of severe hepatitis, but only 5% of patients will develop a chronic infection, with the vast majority evolving to spontaneous clearance of HDV.[23]Botelho-Souza LF Vasconcelos MPA Dos Santos ADO Salcedo JMV Vieira DS Hepatitis delta: Virological and clinical aspects.Virol J. 2017; 14: 1-15https://doi.org/10.1186/s12985-017-0845-yCrossref PubMed Scopus (52) Google Scholar However, when HDV infection is transmitted in the setting of an already established chronic HBV infection (i.e. superinfection), more than 90% of patients will evolve to chronic hepatitis, with a more severe course to cirrhosis.[23]Botelho-Souza LF Vasconcelos MPA Dos Santos ADO Salcedo JMV Vieira DS Hepatitis delta: Virological and clinical aspects.Virol J. 2017; 14: 1-15https://doi.org/10.1186/s12985-017-0845-yCrossref PubMed Scopus (52) Google Scholar Thus, to decipher the role of HDV in liver oncogenesis it is crucial to understand the interaction between both viruses. Longitudinal studies have shown that the long-term interplay between HDV and HBV is complex, with fluctuating levels of HDV RNA and HBV DNA viremia over time and oscillating predominance at different time points.48Schaper M Rodriguez-Frias F Jardi R et al.Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D.J Hepatol. 2010; 52: 658-664https://doi.org/10.1016/j.jhep.2009.10.036Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 49Raimondo G Brunetto MR Pontisso P et al.Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients.Hepatology. 2006; 43: 100-107https://doi.org/10.1002/hep.20944Crossref PubMed Scopus (179) Google Scholar Importantly, in more than 50% of cases, HBV activity is detected at different time points, which has been associated with worse prognosis.[48]Schaper M Rodriguez-Frias F Jardi R et al.Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D.J Hepatol. 2010; 52: 658-664https://doi.org/10.1016/j.jhep.2009.10.036Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar Several mechanisms have been proposed behind HDV-relat" @default.
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• W2945017572 date "2019-08-01" @default.
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• W2945017572 title "The oncogenic role of hepatitis delta virus in hepatocellular carcinoma" @default.
• W2945017572 cites W119762197 @default.
• W2945017572 cites W1480733198 @default.
• W2945017572 cites W1559090356 @default.
• W2945017572 cites W1572584542 @default.
• W2945017572 cites W1582148465 @default.
• W2945017572 cites W1776292783 @default.
• W2945017572 cites W1810525385 @default.
• W2945017572 cites W1814037092 @default.
• W2945017572 cites W1963687802 @default.
• W2945017572 cites W1964252716 @default.
• W2945017572 cites W1964751981 @default.
• W2945017572 cites W1966807894 @default.
• W2945017572 cites W1967901693 @default.
• W2945017572 cites W1970438894 @default.
• W2945017572 cites W1976777085 @default.
• W2945017572 cites W1982604775 @default.
• W2945017572 cites W1986988924 @default.
• W2945017572 cites W1987515540 @default.
• W2945017572 cites W1989671349 @default.
• W2945017572 cites W1990466254 @default.
• W2945017572 cites W1999105154 @default.
• W2945017572 cites W1999374300 @default.
• W2945017572 cites W2007868505 @default.
• W2945017572 cites W2007912885 @default.
• W2945017572 cites W2015755790 @default.
• W2945017572 cites W2017347114 @default.
• W2945017572 cites W2025879508 @default.
• W2945017572 cites W2027032176 @default.
• W2945017572 cites W2028889421 @default.
• W2945017572 cites W2033712837 @default.
• W2945017572 cites W2036201867 @default.
• W2945017572 cites W2043259169 @default.
• W2945017572 cites W2047829320 @default.
• W2945017572 cites W2049268786 @default.
• W2945017572 cites W2058600986 @default.
• W2945017572 cites W2059477215 @default.
• W2945017572 cites W2061219010 @default.
• W2945017572 cites W2069819211 @default.
• W2945017572 cites W2069929606 @default.
• W2945017572 cites W2070569872 @default.
• W2945017572 cites W2075820772 @default.
• W2945017572 cites W2076037594 @default.
• W2945017572 cites W2080628222 @default.
• W2945017572 cites W2090981785 @default.
• W2945017572 cites W2092557025 @default.
• W2945017572 cites W2104239713 @default.
• W2945017572 cites W2104750816 @default.
• W2945017572 cites W2114174543 @default.
• W2945017572 cites W2117380333 @default.
• W2945017572 cites W2119139878 @default.
• W2945017572 cites W2121854581 @default.
• W2945017572 cites W2133202656 @default.
• W2945017572 cites W2139139847 @default.
• W2945017572 cites W2141448996 @default.
• W2945017572 cites W2156666209 @default.
• W2945017572 cites W2158953615 @default.
• W2945017572 cites W2159131506 @default.
• W2945017572 cites W2160046306 @default.
• W2945017572 cites W2161330355 @default.
• W2945017572 cites W2163862465 @default.
• W2945017572 cites W2167460988 @default.
• W2945017572 cites W2167583762 @default.
• W2945017572 cites W2167673078 @default.
• W2945017572 cites W2182891785 @default.
• W2945017572 cites W2255205186 @default.
• W2945017572 cites W2336779096 @default.
• W2945017572 cites W2341442578 @default.
• W2945017572 cites W2406453815 @default.
• W2945017572 cites W2517865904 @default.
• W2945017572 cites W2532957036 @default.
• W2945017572 cites W2538494241 @default.
• W2945017572 cites W2555093284 @default.
• W2945017572 cites W2558087490 @default.
• W2945017572 cites W2605785536 @default.
• W2945017572 cites W2615972323 @default.
• W2945017572 cites W2754708354 @default.
• W2945017572 cites W2755997084 @default.
• W2945017572 cites W2758172374 @default.
• W2945017572 cites W2762103489 @default.
• W2945017572 cites W2775489019 @default.
• W2945017572 cites W2786175833 @default.
• W2945017572 cites W2789818035 @default.
• W2945017572 cites W2791839818 @default.
• W2945017572 cites W2806134350 @default.
• W2945017572 cites W2806413021 @default.
• W2945017572 cites W2856653187 @default.
• W2945017572 cites W2859913083 @default.
• W2945017572 cites W2889169204 @default.
• W2945017572 cites W2891216657 @default.

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