Abstract
Simple SummaryCancer is a major threat to global health, accounting worldwide for nearly 10 million fatalities in 2020. Importantly, carcinogenesis caused by so-called oncoviruses accounts for approximately 10% of the global cancer burden. Specifically, hepatitis B virus, hepatitis C virus and to a lesser extent hepatitis D virus infection have been recognized to be mainly responsible for the occurrence of hepatocellular carcinoma (HCC). Recent studies have further drawn attention to a long-neglected hepatotropic virus, namely hepatitis E virus (HEV), in the context of HCC. Here, we summarize current epidemiological, clinical and experimental studies to unravel a putative link between HEV and HCC and provide an outlook for future scientific efforts in HEV-related HCC research.Hepatitis E virus infections are the leading cause of viral hepatitis in humans, contributing to an estimated 3.3 million symptomatic cases and almost 44,000 deaths annually. Recently, HEV infections have been found to result in chronic liver infection and cirrhosis in severely immunocompromised patients, suggesting the possibility of HEV-induced hepatocarcinogenesis. While HEV-associated formation of HCC has rarely been reported, the expansion of HEV’s clinical spectrum and the increasing evidence of chronic HEV infections raise questions about the connection between HEV and HCC. The present review summarizes current clinical evidence of the relationship between HEV and HCC and discusses mechanisms of virus-induced HCC development with regard to HEV pathogenesis. We further elucidate why the development of HEV-induced hepatocellular carcinoma has so rarely been observed and provide an outlook on possible experimental set-ups to study the relationship between HEV and HCC formation.
Highlights
hepatitis E virus (HEV) has a similar function in hepatocarcinogenesis remains controversial, but several epidemiological and clinical studies imply a potential role of HEV in the Hepatocellular CarcinomaHepatocellular carcinoma (HCC) pathogenesis
The US-American and Chinese studies did not consider the hepatitis B virus (HBV) and HCV status of participants. While all these studies might demonstrate an association between HEV infection and HCC, an epidemiological study from Croatia on the burden of HEV infection in chronic liver disease concluded differently: in a cohort of 438 CLD patients, they did not find a relationship between HEV seropositivity and HCC incidence [44]
Considering all epidemiological data g, it appears that acute HEV infections might be a contributing factor facilitating the progression of chronic liver disease toward HCC in liver tissue already primed for hepatocellular carcinogenesis
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, accounting for about 75–85% of all primary liver malignancies. Risk factors contributing to the development of HCC generally include high alcohol consumption, obesity, hemochromatosis, dietary aflatoxin exposure, type 2 diabetes, smoking, sex (male) and older age (50+) [2,3]. HEV, a hepatotropic RNA virus, causes acute and chronic infection in the human host This capacity—among others—certainly makes HEV a potential oncogenic agent involved in cancer formation. In this review, we summarize and discuss current epidemiological and clinical studies on HCC and HEV infection and potential molecular mechanisms of HEVdriven hepatocarcinogenesis.
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