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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Available from: Mark A Feitelson, Oct 01, 2015
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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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    • "According to International Agency for Research on Cancer (IARC) reports 696,000 people died of liver cancer in the year 2008 alone [1]. Multiple factors have been associated with HCC, however hepatitis B & C virus (HBV and HCV) infections are considered to be the major underlying etiology, as together these viruses account for more than two-thirds of HCC cases worldwide [2]. With around 2 billion people infected with HBV worldwide, of which approximately 350 million are chronic HBV carriers [3], and 170 million infected with HCV [4], HCC poses a major health concern globally. "
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    ABSTRACT: Aberrant DNA methylation profiles are a characteristic feature of almost all types of cancers including hepatocellular carcinoma (HCC) and play an important role in carcinogenesis. In spite of the accumulating evidence that suggests appearance of such aberrations at precancerous stages, very little effort has been invested to investigate such possible methylation events in patients at risk of developing HCC i.e. those suffering from chronic hepatitis C virus (HCV) infection and liver cirrhosis (LC). We reasoned that such an analysis could lead to the identification of novel predictive biomarkers as well as potential drug targets. Promoter methylation status of two Wnt inhibitors SFRP2 and DKK1 was quantitatively analyzed by bisulfite pyrosequencing in a series of liver biopsy samples. These biopsies were collected from HCV-infected individuals suffering from chronic hepatitis (CH; n = 15), liver cirrhosis (LC; n = 13) and hepatocellular carcinoma (HCC; n = 41). DNA isolated from infection free normal livers (N; n =10) was used as control. Our analysis revealed that both of the genomic loci were significantly hypermethylated in CH patients’ livers as compared to normal controls (p = 0.0136 & 0.0084 for SFRP2 and DKK1, respectively; Mann–Whitney U test). DNA methylation levels for both loci were also significantly higher in all the diseased cohorts as compared to normal controls (p < 0.0001 and = 0.0011 for SFRP2 and DKK1, respectively; Kruskal-Wallis test). However, a comparison between three disease cohorts (CH, LC & HCC) revealed no significant difference in levels of DNA methylation at DKK1 promoter. In contrast, a progressive increase in DNA methylation levels was observed at the SFRP2 promoter (i.e. N < CH & LC < HCC). This study demonstrated that in HCV infected liver tissues hypermethylation at promoter regions of key cancer related genes SFRP2 and DKK1, appears early at CH and LC stages, long before the appearance of HCC.
    Virology Journal 06/2014; 11(1):117. DOI:10.1186/1743-422X-11-117 · 2.18 Impact Factor
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