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

Figure 1

A schematic overview shows the impacts of hepatitis B virus and hepatitis C virus proteins in the Wnt signaling pathway. In an inactive state, cytoplasmic β-Catenin interacts with a multiprotein degradation complex comprised of CK1a, APC, GSK3β, and Axin, and following phosphorylation, is targeted for proteasome-dependent degradation. On binding Wnt ligands to FZD and LRP5/6 receptors, the scaffolding protein DVL is recruited to the membrane and phosphorylates GSK3β leading to the disassembly of the β-Catenin destruction complex. This event results in the rescue of β-Catenin from proteasomal degradation leading to its accumulation in the cytoplasm and eventually allowing its translocation to the nucleus. Consequently, β-Catenin activates the transcription of target genes through interaction with TCF and LEF family members. Wnt signaling is regulated by secreted proteins, including SFRPs and DKKs, which inhibit Wnt signaling by binding to FZD and LRP5/6 receptors, respectively. Independent of its transcriptional activity, β-Catenin, forming a complex with E-cadherin, also facilitates cellular junctions between cells. The disintegration of E-cadherin production causes the dissociation of the complex and subsequent internalization of β-Catenin, ending with activation of its target genes. Hepatitis B virus and hepatitis C virus proteins deregulate the expression of various components of the Wnt/β-Catenin pathway and contribute to tumor development and behavior. APC: Adenomatous polyposis coli; CK1: Casein kinase 1a; DKK: Dickkopf family of proteins; DVL: Disheveled segment polarity protein; FZD: Frizzled family of the receptor; GSK3b: Glycogen synthase kinase–3b; LEF: Lymphoid enhancing factor; Lrp5/6: LDL receptor-related protein 5/6; SFRPs: Secreted frizzled-related protein; TCF: DNA-bound T-cell factor; ⊥: Inhibition.

Figure 2

A schematic overview showing the influences of hepatitis B virus and hepatitis C virus proteins on the nuclear factor kappa-Β signaling pathway. Nuclear factor kappa-Β (NF-κB) normally localizes to the cytoplasm and binds to members of the inhibitory IκB family (IκBα, IκBβ, p105, and p100) of proteins, blocking the nuclear translocation of NF-κB. Therefore, deregulation of the IκB family is required for NF-κB to be translocated into the nucleus. Hepatitis B virus and hepatitis C virus use different mechanisms to modulate these transduction pathways by modulating NF-κB proteins activation, interaction with cellular proteins, interaction with other signaling cascades, and ER stress induction. COX-2: Cyclooxygenase-2; ERK: Extracellular signal-regulated kinase; IKK: IκB kinase; IL: Interleukin; JNK: c-Jun N-terminal kinase; p38 MAPK: p38 Mitogen-activated protein kinase; PG: Prostaglandin; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor-α; TNFR: Tumor necrosis factor receptor; ⊥: Inhibition.

Figure 3

Involvement of hepatitis B virus and hepatitis C virus proteins in the Hippo-Make-TAZ signaling pathway. In the cytoplasm, YAP/TAZ proteins are inactivated by phosphorylation leading to their cytoplasmic retention. When YAP/TAZ is dephosphorylated, they can translocate into the nucleus and activate the transcription of their target genes through the interaction with the TEA domain transcription factor Scalloped transcription factors. Additionally, YAP stabilizes CREB through interacting with p38MAPK and beta-transducin repeat containing E3 ubiquitin protein ligase. MEK1 also inhibits the latter. On the other hand, GABP is negatively regulated by the Hippo signaling pathway. AMOT: Actin-associated protein angiomotin; BTRC: Beta-transducin repeat containing E3 ubiquitin protein ligase; CREB: cAMP response element-binding protein; LATS1/2: Large tumor suppressor kinase 1 and 2; MST1/2: Mammalian sterile 20-like kinase 1 and 2; P38 MAPK: P38 mitogen-activated protein kinase; NF2: Neurofibromin 2; SAV1: The adaptor proteins Salvador 1; Scribble: A basolateral polarity factor; TEAD: TEA domain transcription factor Scalloped; TCF4: Transcription factor 4; ⊥: Inhibition.

Figure 4

Schematic overview showing the effects of hepatitis B virus and hepatitis C virus proteins on the functioning of NLR family pyrin domain containing 3 and absent in melanoma 2 inflammasomes. Inflammasome activation is defined by oligomerization of NLR family pyrin domain containing 3 and absent in melanoma 2, which recruits apoptosis-associated speck like proteins and pro-caspase- 1, leading to caspase-1 activation and subsequent conversion of pro-IL- 1β into active IL-1β. HCV: Hepatitis C virus; ASC: Apoptosis-associated speck-like protein containing a CARD; AIM2; Absent in melanoma 2; IL: Interleukin; LPS; Lipopolysaccharides; LBP: Lipopolysaccharide binding protein; NLRP3: NLR family pyrin domain containing 3; TLR: Toll-like receptor; TNFR: TNF receptor; ⊥ : Inhibition.