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      The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis

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          Abstract

          The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.

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          Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

          Huan Yan, Guocai Zhong, Guangwei Xu … (2012)
          Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. DOI: http://dx.doi.org/10.7554/eLife.00049.001
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            Targeting microRNAs in cancer: rationale, strategies and challenges.

            Ramiro Garzon, Guido Marcucci, Carlo Croce (2010)
            MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.
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              The role of signaling pathways in the development and treatment of hepatocellular carcinoma.

              S. Whittaker, R Marais, A X Zhu (2010)
              Hepatocellular carcinoma (HCC) is a highly prevalent, treatment-resistant malignancy with a multifaceted molecular pathogenesis. Current evidence indicates that during hepatocarcinogenesis, two main pathogenic mechanisms prevail: (1) cirrhosis associated with hepatic regeneration after tissue damage caused by hepatitis infection, toxins (for example, alcohol or aflatoxin) or metabolic influences, and (2) mutations occurring in single or multiple oncogenes or tumor suppressor genes. Both mechanisms have been linked with alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective, because targeting them may help to reverse, delay or prevent tumorigenesis. In this review, we explore some of the major pathways implicated in HCC. These include the RAF/MEK/ERK pathway, phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, WNT/beta-catenin pathway, insulin-like growth factor pathway, hepatocyte growth factor/c-MET pathway and growth factor-regulated angiogenic signaling. We focus on the role of these pathways in hepatocarcinogenesis, how they are altered, and the consequences of these abnormalities. In addition, we also review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against these pathways, with early evidence of success.
              Article 0 comments Cited 279 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 24 November 2019
                Publication date Collection: December 2019
                Volume: 8
                Issue: 12
                Electronic Location Identifier: 1504
                Affiliations
                [1 ]Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4041, South Africa; benn.sartorius1@ 123456lshtm.ac.uk (B.S.); chutur@ 123456ukzn.ac.za (A.C.)
                [2 ]Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2193, South Africa
                [3 ]UKZN Gastrointestinal Cancer Research Centre, Durban 4041, South Africa
                [4 ]Hertsen Moscow Oncology Research Institute, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284 Moscow, Russia; j-makarova@ 123456yandex.ru
                [5 ]Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian
                [6 ]Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, 101000 Moscow, Russia
                [7 ]Frederick National Laboratory, Basic Research Laboratory, Centre for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; ping.an@ 123456nih.gov (P.A.); winklerc@ 123456mail.nih.gov (C.W.)
                [8 ]Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa; Anna.Kramvis@ 123456wits.ac.za
                Author notes
                Author information
                https://orcid.org/0000-0002-5322-3510
                https://orcid.org/0000-0003-4649-4133
                https://orcid.org/0000-0001-6006-3765
                Article
                Publisher ID: cells-08-01504
                DOI: 10.3390/cells8121504
                PMC ID: 6953055
                PubMed ID: 31771261
                SO-VID: fc66d5aa-40a7-46ef-a17f-f6b17c0fcf4e
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 07 October 2019
                Date accepted : 12 November 2019
                Categories
                Subject: Review

                Keywords: regulatory,role,dysregulated,mirna,hepatitis b infected hepatocellular carcinoma,hbv-hcc continuum
                Data availability:
                Keywords: regulatory, role, dysregulated, mirna, hepatitis b infected hepatocellular carcinoma, hbv-hcc continuum

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