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The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways
by Kurt Sartorius 1,2,3,*, Leo Swadling 4 [OrcID] , Ping An 5 [OrcID] , Julia Makarova 6 [OrcID] , Cheryl Winkler 5, Anil Chuturgoon 2 [OrcID] and Anna Kramvis 7 [OrcID]
1
Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2050, South Africa
2
Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa
3
UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
4
Division of Infection and Immunity, University College London, London WC1E6BT, UK
5
Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc. Frederick Nat. Lab. for Cancer Research, Frederick, MD 20878, USA
6
National Research University Higher School of Economics, Faculty of Biology and Biotechnology, 10100 Moscow, Russia
7
Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2050, South Africa
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(7), 746; https://doi.org/10.3390/v12070746
Received: 15 June 2020 / Revised: 8 July 2020 / Accepted: 9 July 2020 / Published: 10 July 2020
(This article belongs to the Special Issue Novel Concepts in Virology)
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Abstract
Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.
Keywords: hepatitis B virus; HBx protein; dysregulated; microRNA; hepatocellular carcinoma
1. Background
Hepatitis B virus (HBV) infection is linked with more than 60% of all hepatocellular carcinomas (HCC) in developing countries, compared with 40% in developed countries [1], and HBV has been dubbed “the second most dangerous carcinogen after tobacco” [2,3]. Thus, HBV-associated HCC (HBV-HCC) is a leading cancer in the developing world, especially so in Africa and Asia [4]. This variant of liver carcinoma triggers a range of immune response failures that includes the dysregulation of microRNA (miRNA) [5]. miRNA provide an additional ‘layer’ of control in the immune system [6] by exerting a mild homeostatic effect on protein transcription and translation by way of suppressing complementary mRNA sequences. miRNA “see” their target by matching their nucleotide sequence to the 3′ untranslated region (UTR) of its target mRNA, whereas immune cells use selective cell surface receptors to bind with target antigens. In effect, multiple miRNA are activated in the presence of disease to collectively inhibit the mRNA expression of targeted genes in order modulate their expression. The ancillary role of miRNA, which can be described as mild suppressors acting in support of the immune system, helps to maintain homeostasis of the dynamic systems within which they operate [7].
Hepatitis B X protein (HBx)-induced dysregulation of host miRNA in the various HBV-HCC pathways [8] can contribute to the ability of HBV to evade and control the host immune system for its own purposes of replication. This modulation can result in miRNA losing their role as part of an ancillary immune system because they are commandeered to modulate host and viral expression in favor of the virus [9]. The principal purpose of this exploratory review is to illustrate the complex role of some key miRNA that are dysregulated by the HBx protein in the HBV-HCC continuum, as well as in both the innate and adaptive immune cells. In this regard, our focus is to demonstrate how the HBx protein can dysregulate miRNA in hepatocytes in HBV-HCC pathogenesis and how this can simultaneously trigger changes in the same miRNA expression in innate and adaptive immune cell pathways. This is the connection we seek to make, namely, that in HBV-HCC pathogenesis the miRNA response in immune cells is not independent of their expression in hepatocytes. We, therefore, hypothesize that in HBV-HCC pathogenesis specific HBx-dysregulated miRNA in hepatocytes also become dysregulated in immune cells because of the influence of viral infection. This review provides a platform for multiple hypotheses for future studies. |
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