The liver is frequently exposed to toxins, metabolites, and oxidative stress, which can challenge organ function and genomic stability. Liver regeneration is therefore a highly regulated process involving several sequential signaling events. It is thus not surprising that individual oncogenic mutations in hepatocytes do not necessarily lead to cancer and that the genetic profiles of hepatocellular carcinomas (HCCs) are highly heterogeneous. Long-term infection with hepatitis C virus (HCV) creates an oncogenic environment by a combination of viral protein expression, persistent liver inflammation, oxidative stress, and chronically deregulated signaling events that cumulate as a tipping point for genetic stability. Although novel direct-acting antivirals (DAA)-based treatments efficiently eradicate HCV, the associated HCC risk cannot be fully eliminated by viral cure in patients with advanced liver disease. This suggests that HCV may persistently deregulate signaling pathways beyond viral cure and thereby continue to perturb cancer-relevant gene function. In this review, we summarize the current knowledge about oncogenic signaling pathways derailed by chronic HCV infection. This will not only help to understand the mechanisms of hepatocarcinogenesis but will also highlight potential chemopreventive strategies to help patients with a high-risk profile of developing HCC.

Chronic viral hepatitis is a main cause of liver disease and hepatocellular carcinoma. There are striking similarities in the pathological impact of hepatitis B, C, and D, although these diseases are caused by very different viruses. Paired with the conventional study of protein–host interactions, the rapid technological development of -omics and bioinformatics has allowed highlighting the important role of signaling networks in viral pathogenesis. In this review, we provide an integrated look on the three major viruses associated with chronic viral hepatitis in patients, summarizing similarities and differences in virus-induced cellular signaling relevant to the viral life cycles and liver disease progression.

Despite breakthroughs in antiviral therapies, chronic viral hepatitis B and C are still the major causes of liver fibrosis and hepatocellular carcinoma (HCC). Importantly, even in patients with controlled infection or viral cure, the cancer risk cannot be fully eliminated, highlighting a persisting oncogenic pressure imposed by epigenetic imprinting and advanced liver disease. Reliable and minimally invasive biomarkers for early fibrosis and for residual HCC risk in HCV-cured patients are urgently needed. Chronic infection with HBV and/or HCV dysregulates oncogenic and profibrogenic signaling within the host, also displayed in the secretion of soluble factors to the blood. The study of virus-dysregulated signaling pathways may, therefore, contribute to the identification of reliable minimally invasive biomarkers for the detection of patients at early-stage liver disease potentially complementing existing noninvasive methods in clinics. With a focus on virus-induced signaling events, this review provides an overview of candidate blood biomarkers for liver disease and HCC risk associated with chronic viral hepatitis and epigenetic viral footprints.

Chronic hepatitis C carries a high risk of development of hepatocellular carcinoma (HCC), triggered by both direct and indirect effects of the virus. We examined cell-autonomous alterations in gene expression profiles associated with hepatitis C viral presence. Highly sensitive single molecule fluorescent in situ hybridization applied to frozen tissue sections of a hepatitis C patient allowed the delineation of clusters of infected hepatocytes. Laser microdissection followed by RNAseq analysis of hepatitis C virus (HCV)-positive and -negative regions from the tumoral and non-tumoral tissues from the same patient revealed HCV-related deregulation of expression of genes in the tumor and in the non-tumoral tissue. However, there was little overlap between both gene sets. Our interest in alterations that increase the probability of tumorigenesis prompted the examination of genes whose expression was increased by the virus in the non-transformed cells and whose level remained high in the tumor. This strategy led to the identification of a novel HCV target gene: GOLT1B, which encodes a protein involved in ER-Golgi trafficking. We further show that GOLT1B expression is induced during the unfolded protein response, that its presence is essential for efficient viral replication, and that its expression is correlated with poor outcome in HCC.