HBV-related hepatocarcinogenesis: the role of signalling pathways and innovative ex vivo research models

Abstract

Background Hepatitis B virus (HBV) is the leading cause of liver cancer, but the mechanisms by which HBV causes liver cancer are poorly understood and chemotherapeutic strategies to cure liver cancer are not available. A better understanding of how HBV requisitions cellular components in the liver will identify novel therapeutic targets for HBV associated hepatocellular carcinoma (HCC). Main body The development of HCC involves deregulation in several cellular signalling pathways including Wnt/FZD/β-catenin, PI3K/Akt/mTOR, IRS1/IGF, and Ras/Raf/MAPK. HBV is known to dysregulate several hepatocyte pathways and cell cycle regulation resulting in HCC development. A number of these HBV induced changes are also mediated through the Wnt/FZD/β-catenin pathway. The lack of a suitable human liver model for the study of HBV has hampered research into understanding pathogenesis of HBV. Primary human hepatocytes provide one option; however, these cells are prone to losing their hepatic functionality and their ability to support HBV replication. Another approach involves induced-pluripotent stem (iPS) cell-derived hepatocytes. However, iPS technology relies on retroviruses or lentiviruses for effective gene delivery and pose the risk of activating a range of oncogenes. Liver organoids developed from patient-derived liver tissues provide a significant advance in HCC research. Liver organoids retain the characteristics of their original tissue, undergo unlimited expansion, can be differentiated into mature hepatocytes and are susceptible to natural infection with HBV. Conclusion By utilizing new ex vivo techniques like liver organoids it will become possible to develop improved and personalized therapeutic approaches that will improve HCC outcomes and potentially lead to a cure for HBV.

The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling

“…It remains to be determined if this localized hyperactive Wnt signaling is due to loss of transcriptional repression or activation of transcription. Further investigation of the p22 mechanism of action in ex vivo models systems for example that do not have the limitations of continuous, transformed cell lines and mouse models with respect to human disease [27], might reveal novel avenues of research to help identify new components to selectively harness different aspects of Wnt signaling; for example, blocking oncogenic Wnt signaling while preserving the critical role Wnt signaling provides to ensure the correct regulation of stem cells and homeostasis of many epithelial tissues. Selective regulation of Wnt signaling is at the core of identifying druggable Wnt pathway targets, as the desired outcome for a cancer specific drug that inhibits Wnt is for the drug to allow normal physiological processes to proceed thus reducing the toxicity of a blanket approach of inhibiting Wnt signaling.…”

Downregulation of HBx Restrains Proliferation, Migration and Invasion of HepG2 Cells

“…HBV has been suggested to signi cantly induce liver cancer [16]. However, the underlying regulatory mechanism of HBV-infected liver cancer has not been fully elaborated.…”

Bioinformatic Identification and Validation of Key Genes and Biological Pathways Involved in Hepatitis B Virus-related Hepatocellular Carcinoma

“…All the above results show that the progression in cell cycle has a close relationship with HBV-HCC. These gene functions and the signaling pathways might interact with HBV and corporately affect the development of HCC, especially by regulating the cell cycles and proliferation [15]. Xia et al found that HBV parvoviral host factors (such as PPARA, CEBPB and RXRA) were upregulated upon infection and enriched in primary human hepatocytes in the G2/M phase, which supports that HBV may promote viral replication and a premalignant phenotype that predisposes infected hepatocytes to subsequent malignant transformation by deregulating the cell cycle [16].…”