The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets

Abstract

Chronic hepatitis B virus (HBV) infection remains the number one risk factor for hepatocellular carcinoma (HCC), accounting for more than 600 000 deaths/year. Despite highly effective antiviral treatment options, chronic hepatitis B (CHB), subsequent end-stage liver disease and HCC development remain a major challenge worldwide. In CHB, liver damage is mainly caused by the influx of immune cells and destruction of infected hepatocytes, causing necro-inflammation. Treatment with nucleoside/nucleotide analogues can effectively suppress HBV replication in patients with CHB and thus decrease the risk for HCC development. Nevertheless, the risk of HCC in treated patients showing sufficient suppression of HBV DNA replication is significantly higher than in patients with inactive CHB, regardless of the presence of baseline liver cirrhosis, suggesting direct, long-lasting, predisposing effects of HBV. Direct oncogenic effects of HBV include integration in the host genome, leading to deletions, cis/trans-activation, translocations, the production of fusion transcripts and generalized genomic instability, as well as pleiotropic effects of viral transcripts (HBsAg and HBx). Analysis of these viral factors in active surveillance may allow early identification of high-risk patients, and their integration into a molecular classification of HCC subtypes might help in the development of novel therapeutic approaches.

Epidemiology and viral risk factors for hepatocellular carcinoma in the Eastern Mediterranean countries

“…China has the highest incidence of HCC in the world, accounting for more than 40% of all HCC cases and 55% of liver cancer deaths [3,4] . Southern European countries have an intermediateincidence (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) cases per 100,000 population/year); while North America, South America, Northern Europe, and parts of Middle East have low-incidence rates (< 5 cases per 100,000 population/year) [3][4][5] . The incidence in Asian countries tends to decline in the past 2 decades whilst it increased in United States and Canada because of high rate of chronic hepatitis C virus (HCV)-related cirrhosis, nonalcoholic fatty liver disease and immigrants from HBV endemic regions [4] .…”

“…In persons chronically infected with HBV, the risk of HCC has been shown to increase up to 30-fold [14,15] . As a result of hepatic inflammation and liver damage, genetic and epigenetic defects lead to development of HCC [16][17][18] . However, in the absence of cirrhosis HCC can develop in 10%-20% of HBV-infected individuals as a result of integration of HBV into the host genome that induces chromosomal alterations and insertional mutagenesis of cancer genes [17][18][19] .…”

“…As a result of hepatic inflammation and liver damage, genetic and epigenetic defects lead to development of HCC [16][17][18] . However, in the absence of cirrhosis HCC can develop in 10%-20% of HBV-infected individuals as a result of integration of HBV into the host genome that induces chromosomal alterations and insertional mutagenesis of cancer genes [17][18][19] . The genetic instability of the hepatocyte triggers the clonal growth of hepatocytes before the liver damage occurs.…”

Emerging role of microRNAs in the treatment of hepatocellular carcinoma

“…38 Moreover, upregulated gene, upregulation of which is induced by HBx, could induce miR-148a overexpression and promote cell cycle progression and cell migration. 39,40 The mechanisms of miRNA deregulation by hepatitis C virus have been less extensively studied. 41 MiR-141 upregulation, which has been described in hepatitis C virus-infected human hepatocytes in vitro, causes the depletion of DLC-1 protein, a tumor suppressor frequently deleted in HCC.…”

Immunotherapy against cancer-related viruses

“…Second, viral infection can lead to cancer by inducing chronic inflammation [4]. For example, HBV and HCV induce chronic hepatic inflammation associated with oxidative DNA damage followed by macronodular cirrhosis, contributing to the subsequent development of hepatocellular carcinoma (HCC) [5][6]. Finally, some viruses such as HIV are not themselves oncogenic but inhibit the patient's immune system, disrupting immunosurveillance and allowing for the emergence of hyper-mutated malignant cells [7].…”