Hepatitis B Virus-Associated Hepatocellular Carcinoma and Hepatic Cancer Stem Cells

Abstract

Chronic Hepatitis B Virus (HBV) infection is linked to hepatocellular carcinoma (HCC) pathogenesis. Despite the availability of a HBV vaccine, current treatments for HCC are inadequate. Globally, 257 million people are chronic HBV carriers, and children born from HBV-infected mothers become chronic carriers, destined to develop liver cancer. Thus, new therapeutic approaches are needed to target essential pathways involved in HCC pathogenesis. Accumulating evidence supports existence of hepatic cancer stem cells (hCSCs), which contribute to chemotherapy resistance and cancer recurrence after treatment or surgery. Understanding how hCSCs form will enable development of therapeutic strategies to prevent their formation. Recent studies have identified an epigenetic mechanism involving the downregulation of the chromatin modifying Polycomb Repressive Complex 2 (PRC2) during HBV infection, which results in re-expression of hCSC marker genes in infected hepatocytes and HBV-associated liver tumors. However, the genesis of hCSCs requires, in addition to the expression of hCSC markers cellular changes, rewiring of metabolism, cell survival, escape from programmed cell death, and immune evasion. How these changes occur in chronically HBV-infected hepatocytes is not yet understood. In this review, we will present the basics about HBV infection and hepatocarcinogenesis. Next, we will discuss studies describing the mutational landscape of liver cancers and how epigenetic mechanisms likely orchestrate cellular reprograming of hepatocytes to enable formation of hCSCs.

Keywords: Epigenetics; Epithelial Cell Adhesion Molecule (EpCAM); Hepatitis B Virus (HBV); Hepatocellular Carcinoma (HCC); Hox transcript antisense RNA (HOTAIR); Polycomb Repressive Complex 2 (PRC2); hepatic Cancer Stem Cells (hCSCs); p68/DDX5 RNA helicase; pluripotency genes.

Figure 1

Hepatitis B Virus (HBV) Genome Organization. The innermost two black lines represent the full-length minus (–) strand (with the terminal protein attached to its 5′ end) and the incomplete plus (+) strand. The outer black lines represent the 3.5, 2.4, 2.1 and 0.7 kb mRNA transcripts. The outermost lines indicate the translated HBV proteins.

Figure 2

HBV Life Cycle. HBV uses the Sodium Taurocholate Co-transporting Polypeptide (NTCP) receptor to attach to hepatocytes. After entry, HBV nucleocapsids transport the HBV DNA to the nucleus, where the relaxed circular DNA is converted into covalently closed circular (ccc) DNA. The cccDNA assumes a minichromosome-like structure and acts as the template for transcription of four viral RNAs (0.7 kb, 2.1 kb, 2.4 kb and 3.5 kb). The mRNA transcripts are exported to the cytoplasm and used for translation of the HBV proteins. The longest (pre-genomic) RNA also functions as the template for replication, which occurs within nucleocapsids in the cytoplasm. Nucleocapsids are enveloped during their passage through the endoplasmic reticulum (ER) and/or Golgi complex and secreted from the cell. HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen, HBx: Hepatitis B X protein.

Figure 3

Proposed model: DDX5 in association with the PRC2 complex could coordinate via epigenetic mechanisms expression of different cascades of signaling pathways that ultimately could bring about the hCSC phenotype. The relevant pathways are shown.