乙型肝炎病毒X蛋白（HBx）失调的MicroRNA在乙型肝炎病毒相关

StephenW

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.

StephenW

乙型肝炎病毒X蛋白（HBx）失调的MicroRNA在乙型肝炎病毒相关的肝细胞癌（HBV-HCC）和免疫途径中的多重作用
作者：Kurt Sartorius 1,2,3，*，Leo Swadling 4 [OrcID]，平安5 [OrcID]，Julia Makarova 6 [OrcID]，Cheryl Winkler 5，Anil Chuturgoon 2 [OrcID]和Anna Kramvis 7 [OrcID]
1个
威特沃特斯兰德大学商业，法律与管理学院，南非约翰内斯堡2050
2
夸祖鲁-纳塔尔大学护理与公共卫生学院公共卫生系，南非德班4041
3
UKZN胃肠道癌研究中心，南非德班4041
4
伦敦大学学院感染与免疫学系，英国伦敦WC1E6BT，英国
5
Leidos Biomedical Research，Inc.国家癌症研究所，癌症研究中心基础研究实验室。Frederick Nat。实验室美国癌症研究基金会，弗雷德里克，医学博士20878
6
国立研究大学高等经济学院，生物与生物技术学院，俄罗斯莫斯科10100
7
威特沃特斯兰德大学健康科学学院临床医学院内科肝炎病毒多样性研究室，南非约翰内斯堡2050
*
应与之联系的作者。
病毒2020，12（7），746; https://doi.org/10.3390/v12070746
收到：2020年6月15日/修订：2020年7月8日/接受：2020年7月9日/发布：2020年7月10日
（本文属于病毒学特刊小说概念）
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抽象
当前，与乙型肝炎病毒（HBV）相关的肝细胞癌（HCC）[HBV-HCC]的治疗依赖于钝器，这些钝器无法为晚期发病机理提供有效的治疗方法。 miRNA在治疗HBV-HCC中的潜力为治疗这种致命癌提供了更具针对性的方法。然而，miRNA作为免疫系统辅助调节剂的复杂性仍然知之甚少。这篇综述检查了HBx失调的miRNA在HBV-HCC和免疫途径中的重叠作用，并试图证明免疫细胞中的特定miRNA反应并不独立于其在肝细胞中的表达。两种途径之间的相互作用可能为我们提供了使用候选miRNA操纵这种相互作用作为潜在治疗选择的可能性。
关键词：乙型肝炎病毒； HBx蛋白;失调微小RNA肝细胞癌
1.背景
在发展中国家，乙型肝炎病毒（HBV）感染与所有肝细胞癌（HCC）的比例超过60％，而在发达国家，这一比例为40％[1]，并且乙肝病毒被称为“仅次于烟草的第二大危险致癌物” [2,3]。因此，与乙肝病毒相关的肝癌（HBV-HCC）是发展中国家的主要癌症，尤其是在非洲和亚洲[4]。肝癌的这种变异引发一系列免疫反应失败，包括microRNA（miRNA）异常[5]。 miRNA通过抑制互补的mRNA序列对蛋白质的转录和翻译产生适度的稳态作用，从而在免疫系统中提供了额外的“控制层” [6]。 miRNA通过使核苷酸序列与其靶标mRNA的3'非翻译区（UTR）匹配来“看到”其靶标，而免疫细胞使用选择性细胞表面受体与靶标抗原结合。实际上，多种miRNA在疾病存在下被激活，共同抑制靶基因的mRNA表达，从而调节其表达。 miRNA的辅助作用可被描述为轻度抑制剂，可支持免疫系统，有助于维持其运作所在的动态系统的动态平衡[7]。
乙型肝炎X蛋白（HBx）诱导的各种HBV-HCC途径中宿主miRNA的失调[8]可能有助于HBV出于自身复制目的逃避和控制宿主免疫系统的能力。这种调节可能导致miRNA失去其作为辅助免疫系统一部分的作用，因为它们被命令调节宿主和病毒的表达以支持病毒[9]。这项探索性综述的主要目的是说明在HBV-HCC连续体以及先天和适应性免疫细胞中HBx蛋白失调的一些关键miRNA的复杂作用。在这方面，我们的重点是证明HBx蛋白如何在HBV-HCC发病机理中失调肝细胞中的miRNA，以及它如何同时触发先天性和适应性免疫细胞途径中相同miRNA表达的变化。这就是我们试图建立的联系，即在HBV-HCC发病机理中，免疫细胞中的miRNA反应并不独立于其在肝细胞中的表达。因此，我们假设在HBV-HCC发病机理中，由于病毒感染的影响，肝细胞中特异性HBx失调的miRNA在免疫细胞中也会失调。这篇综述为将来的研究提供了多种假设的平台。

StephenW

https://www.mdpi.com/1999-4915/12/7/746/htm