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.
Highlights
hepatocellular carcinoma (HCC) is the fifth most common human cancer and the third leading cause of cancerrelated death worldwide [1]
In a previous study performed by our group in hepatitis C virus (HCV)-HCC, a significant drop in HCV RNA was exclusively associated with malignant hepatocytes, whereas the levels of HCV replication in serum were similar between cirrhotic patients with HCC and those with non-HCC [41]
hepatitis D virus (HDV) replicates in the nucleus of hepatocytes, and, through its ability to interact with several cellular proteins and to modulate their expression, it may alter multiple cellular signaling pathways involved in inflammation, oxidative stress, apoptosis, and cellular proliferation
Summary
HCC is the fifth most common human cancer and the third leading cause of cancerrelated death worldwide [1]. HBsAg carriers are coinfected with HDV worldwide [7], recent studies have suggested either a higher number, between 42 and 72 million [8,9], or a lower number of around 12 million [10]. These different estimates reflect the wide heterogeneity in the recruitment of patients, as well as differences in methodologies used for the diagnosis. We will discuss the uniqueness of HDV, the risk of developing HCC in the natural history of chronic hepatitis D compared to HBV monoinfection, and the potential molecular mechanisms of HDV hepatocarcinogenesis
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