Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma

Department of Biology and Sbarro Health Research Organization, College of Science and Technology, Temple University, 1900 N. 12th Street, Philadelphia, Pennsylvania 19122, USA.
Nature Reviews Cancer (Impact Factor: 37.4). 12/2012; 13(2):123-35. DOI: 10.1038/nrc3449
Source: PubMed


Hepatocellular carcinoma (HCC) is a highly lethal cancer, with increasing worldwide incidence, that is mainly associated with chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections. There are few effective treatments partly because the cell- and molecular-based mechanisms that contribute to the pathogenesis of this tumour type are poorly understood. This Review outlines pathogenic mechanisms that seem to be common to both viruses and which suggest innovative approaches to the prevention and treatment of HCC.

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    • "Viral hepatitis represents a major health problem worldwide, with hundreds of millions of chronic carriers who have a high risk of developing liver cirrhosis and hepatocellular carcinoma [1]. To establish and maintain persistent replication, hepatitis B virus (HBV) has evolved multiple strategies to evade the host innate and adaptive immune responses [2]. "
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    ABSTRACT: The outcome of Hepatitis B virus infection may be influenced by early interactions between the virus and hepatocyte innate immune responses. To date, the study of such interactions during the very early step of infection has not been adequately investigated. We used the HepaRG cell line, as well as primary human hepatocytes to analyze, within 24 hours of exposure to HBV, either delivered by a physiologic route or baculovirus vector (Bac-HBV), the early modulation of the expression of selected antiviral/pro-inflammatory cytokines and interferon-stimulated-genes. Experiments were also performed in presence or absence of innate receptor agonists to investigate early HBV-induced blockade of innate responses. We show that hepatocytes themselves could detect HBV, and express innate genes when exposed to either HBV virions or Bac-HBV. Whereas Bac-HBV triggered a strong antiviral cytokine secretion followed by the clearance of replicative intermediates, a physiologic HBV exposure led to an abortive response. The early inhibition of innate response by HBV was mainly evidenced on TLR3 and RIG-I/MDA5 signaling pathways upon engagement with exogenous agonist, leading to a decreased expression of several pro-inflammatory and antiviral cytokine genes. Finally, we demonstrate that this early inhibition of dsRNA-mediated response is due to factor(s) present in the HBV inoculum, but not being HBsAg or HBeAg themselves, and does not require de novo viral protein synthesis and replication. Our data provide strong evidence that HBV viral particles themselves can readily inhibit host innate immune responses upon virion/cell interactions, and may explain, at least partially, the "stealthy" character of HBV. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 07/2015; DOI:10.1016/j.jhep.2015.07.014 · 11.34 Impact Factor
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    • "The putative mechanisms of how antiviral therapy reduces HCC risk may include downregulation of hepatic inflammation and related nuclear signaling pathways that lead to neoplastic transformation at the cellular level, as well as reversal of fibrosis and reduction of regenerative stimuli at the tissue level. Antiviral therapy may also reduce expression of HBx protein to levels insufficient to promote HCC development, or act at a genomic level by preventing HBV DNA integration into host chromosomes or affecting its malignant potential [3] [4] [5]. "
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    ABSTRACT: In the treatment of chronic hepatitis B (CHB), the ultimate goal is preventing hepatitis B virus (HBV)-associated liver disease, including hepatocellular carcinoma (HCC). Recently published studies show that in CHB patients treated with the currently recommended first-line nucleos(t)ide analogs (NAs) entecavir or tenofovir, annual HCC incidences range from 0.01-1.4% in non-cirrhotic patients, and from 0.9-5.4% in those with cirrhosis. In Asian studies including matched untreated controls, current NA therapy consistently resulted in a significantly lower HCC incidence in patients with cirrhosis, amounting to an overall HCC risk reduction of ∼30%; in non-cirrhotic patients, HCC risk reduction was overall ∼80%, but was observed in some studies only. For patients of Caucasian origin, no appropriate comparative studies are available to date to evaluate the impact of NA treatment on HCC. Achievement of a virologic response under current NA therapy was associated with a lower HCC risk in Asian, but not Caucasian studies. Studies comparing entecavir or tenofovir with older NAs generally found no difference in HCC risk reduction between agents, except for one study which used no rescue therapy in patients developing lamivudine resistance. Overall, these data indicate that with the current, potent NAs, HCC risk can be reduced but not eliminated, probably due to risk factors that are not amenable to change by antiviral therapy, or events that may have taken place before treatment initiation. Validated pre- and on-therapy HCC risk calculators that inform the best practice for HCC surveillance and facilitate patient counseling would be of great practical value. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 01/2015; 62(4). DOI:10.1016/j.jhep.2015.01.002 · 11.34 Impact Factor
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    • "The most frequent etiology of HCC is chronic hepatitis B and C (CHB, CHC), or alcoholic liver disease. Although recent advances in functional genomics provide a deeper understanding of viral associated hepatocarcinogenesis (review in [6]), the molecular pathogenesis of HCC remains unclear. "
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    ABSTRACT: MicroRNA (miRNA) expression profiling has proven useful in diagnosing and understanding the development and progression of several diseases. Microarray is the standard method for analyzing miRNA expression profiles; however, it has several disadvantages, including its limited detection of miRNAs. In recent years, advances in genome sequencing have led to the development of next-generation sequencing (NGS) technologies, which significantly advance genome sequencing speed and discovery. In this study, we compared the expression profiles obtained by next generation sequencing (NGS) with the profiles created using microarray to assess if NGS could produce a more accurate and complete miRNA profile. Total RNA from 14 hepatocellular carcinoma tumors (HCC) and 6 matched non-tumor control tissues were sequenced with Illumina MiSeq 50-bp single-end reads. Micro RNA expression profiles were estimated using miRDeep2 software. As a comparison, miRNA expression profiles for 11 out of 14 HCCs were also established by microarray (Agilent human microRNA microarray). The average total sequencing exceeded 2.2 million reads per sample and of those reads, approximately 57% mapped to the human genome. The average correlation for miRNA expression between microarray and NGS and subtraction were 0.613 and 0.587, respectively, while miRNA expression between technical replicates was 0.976. The diagnostic accuracy of HCC, p-value, and AUC were 90.0%, 7.22×10−4, and 0.92, respectively. In summary, NGS created an miRNA expression profile that was reproducible and comparable to that produced by microarray. Moreover, NGS discovered novel miRNAs that were otherwise undetectable by microarray. We believe that miRNA expression profiling by NGS can be a useful diagnostic tool applicable to multiple fields of medicine.
    PLoS ONE 09/2014; 9(9):e106314. DOI:10.1371/journal.pone.0106314 · 3.23 Impact Factor
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