Hepatitis D Virus and Hepatocellular Carcinoma

Abstract

Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.

Hepatitis B Virus-Associated Hepatocellular Carcinoma

“…A meta-analysis showed a significantly increased risk of HCC in patients with chronic HDV hepatitis (CHD), with a pooled OR of 1.28 (95% CI 1.05–1.57; I2 = 67.0%), which increased to 2.77 in the absence of heterogeneity for prospective cohort studies (95% CI 1.79–4.28; I2 = 0%), compared to HBV monoinfection [ 98 ]. Nonetheless, data on the genomic signature of HDV or on the levels of HDV replication into the tumor are still lacking [ 99 ]. In a study conducted in Caucasian patients with HDV-HCC, gene expression was performed comparing malignant and non-malignant hepatocytes, reporting a molecular profile, which suggest that the molecular signature of HDV-HCC is different from HBV-HCC [ 100 ].…”

Experimental Models of Hepatocellular Carcinoma—A Preclinical Perspective

“…In contrast, HCV infection and nonalcoholic fatty liver disease (NAFLD) are major risk factors associated with HCC in western countries [1,16]. Another infectious factor considered to augment the risk of developing HCC is represented by the Hepatitis D-delta virus (HDV), a hybrid virus that acts as a satellite of HBV by incorporating the HBV surface antigen (HBsAg) and infecting only the persons that present an infection with HBV [17]. In addition, exposure to the Aspergillus-derived aflatoxin, obesity, smoking, oral contraception use, and alcohol intake are primary risk factors contributing to liver carcinogenesis [15,18].…”

Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma

“…In particular, the signaling cascades activated by G-protein coupled receptors and receptor tyrosine kinases like EGFR, namely the mitogen-activated protein kinase (MAPK)/ERK (or Ras/Raf/MEK/ERK) and PI3K/AKT/mTOR pathways, have been identified to be involved in the oncogenic process [ 65 ]. Interestingly, numerous studies conducted on HBV-, HDV- and HCV-associated HCC have been unraveling how deregulation of these cellular pathways by viral proteins drives hepatocarcinogenesis (i.e., reviewed in [ 66 , 67 , 68 ]). Interestingly, several studies have identified tumorigenesis pathways to be deregulated by HEV infection.…”