Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update

Abstract

Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.

Keywords: Hepatitis B virus, Hepatitis C virus, Hepatocellular carcinoma, Carcinogenesis, Molecular pathways, Viral hepatitis.

Core Tip: Hepatocellular carcinoma remains an aggressive tumor, despite extensive studies on its ontogeny and prognosis. Although the occurrence of this tumor in both hepatitis B virus (HBV) and hepatitis C virus (HCV) backgrounds indicates the effect of persistent inflammation in malignant transformation, the viral effects are not limited to the impaired microenvironment. Recent studies have revealed complex mechanisms that reflect concerted and cumulative effects of chronic inflammation-related alterations, modification of oncogenic pathways (especially tumor suppression, proliferation, and apoptosis), and epigenetic dysregulation driven by both HBV and HCV. In addition, the integration of HBV into host DNA may also affect tumor development and behavior.