Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.
Highlights
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, have liver cirrhosis [1], the severity of which can prevent effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC [2,3,4,5,6,7]
Among upstream genes associated with the histone-modification pathway, somatic mutations and copy number alterations in nuclear receptor corepressor 1 (NCOR1) are present in 2% and 29% of cases, respectively; those in SRCAP are present in 3% and 10% of cases, respectively; those in SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) are present in 2% and
A previous study showed that a truncated mutant of HBV surface antigen (HBsAg) increases Hepatitis B virus (HBV)-related tumorigenesis in a mechanism potentially associated with the downregulated expression of tumor growth factor (TGF)BI associated with the TGFβ–SMAD pathway [153]
Summary
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, have liver cirrhosis [1], the severity of which can prevent effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC [2,3,4,5,6,7]. Because most patients with liver cirrhosis are asymptomatic, it is difficult to diagnose early stages of HCC [8], and patients with hepatic symptoms and HCC are considered to have advanced-stage HCC [8,9]. These issues explain the prevalence of poor prognosis for HCC patients. Hepatitis B virus (HBV) infection is associated with the higher HCC incidence in persons with cirrhosis, occurring in high endemic areas and in Western countries (5-year cumulative incidence, 15% and 10%, respectively) [11]. Nwoitlal bhleyl,p~c7l0in%icoiafnHsCdCiagpnaotiseenatsndartereaafflt ipcatetidenwtsitwh iHthBlVivoerr HcirCrVhoisnifseacntido/nor[1H1]C; Cthienretfhoerier,dwaeilyfoccluinsiecdalopnrtahceticoec.cNurorteanbcley,o~f7H0%CCofdHurCinCgpHatBieVntasnadreHaCffVlicitnefdecwtiiotnh (HFiBgVuroer1H).CV infection [11]; we focused on the occurrence of HCC during HBV and HCV infection (Figure 1)
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