Microarray analyses and molecular profiling of Stat3 signaling pathway induced by hepatitis C virus core protein in human hepatocytes (original) (raw)
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performed to identify a gene expression signature of liver disease. The expression levels of approximately 13,600 genes were analyzed using surgical material and core biopsy specimens from HCV-infected cirrhotic liver explants in comparison with reference samples of normal nondiseased liver. In addition, normal liver samples were compared with each other to determine normal physiologic variation in gene expression. A set of genes, including some associated with stress, acute-phase immune response, and hepatic stellate cell activation, had variable expression levels in normal livers. These genes were subtracted from the sets of genes differentially expressed in cirrhotic livers. To exclude cancer-related genes from our marker sets, we subtracted genes that also were expressed differentially in hepatocellular carcinomas.
Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma
Journal of Translational Medicine, 2009
Background: Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The molecular mechanisms of HCV-induced hepatocarcinogenesis are not yet fully elucidated. Besides indirect effects as tissue inflammation and regeneration, a more direct oncogenic activity of HCV can be postulated leading to an altered expression of cellular genes by early HCV viral proteins. In the present study, a comparison of gene expression patterns has been performed by microarray analysis on liver biopsies from HCV-positive HCC patients and HCV-negative controls.
Microarray analyses and molecular profiling of steatosis induction in immortalized human hepatocytes
Laboratory Investigation, 2007
Hepatitis C virus (HCV) infection is a major contributor to the development of end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC). We have previously shown that HCV core protein promotes immortalization of primary human hepatocytes. To identify molecular changes involved in core protein-mediated immortalization, we have investigated differential gene expression by microarray analyses in primary human hepatocytes and HCV core gene introduced hepatocytes after senescence (early passage), immortalization (middle passage), and anchor-independent growth (late passage). Out of 33,000 human genes screened, 1918 transcripts were differentially expressed (>2-fold) in immortalized human hepatocytes (IHH) as compared to negative controls. Our analyses provided a molecular portrait of changes in gene expression associated with three distinct stages of hepatocytes after introduction of HCV core gene. Many of the overall changes were involved with important cellular pathways, including cell growth regulation, immune regulation, oxidative stress, and apoptosis. We focused on the Stat3 signaling pathway by further verifying selected genes at the protein level relevant to hepatocyte growth regulation. Our data suggested that the introduction of HCV core protein results in an increase in expression of IL-6, gp130, leptin receptor, and Stat3. Upregulation of these genes in turn may regulate c-myc and cyclin D1, downstream of the Stat3 signaling pathway. Identification of these modulated genes with potential roles may help in the selection of targets for therapies against HCV-mediated liver disease progression.
Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma
Hepatology, 2007
Although HCC is the third-leading cause of cancer-related deaths worldwide, there is only an elemental understanding of its molecular pathogenesis. In western countries, HCV infection is the main etiology underlying this cancer's accelerating incidence. To characterize the molecular events of the hepatocarcinogenic process, and to identify new biomarkers for early HCC, the gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC, including 4 neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. We identified gene signatures that accurately reflect the pathological progression of disease at each stage. Eight genes distinguish between control and cirrhosis, 24 between cirrhosis and dysplasia, 93 between dysplasia and early HCC, and 9 between early and advanced HCC. Using quantitative real-time reverse-transcription PCR, we validated several novel molecular tissue markers for early HCC diagnosis, specifically induction of abnormal spindle-like, microcephaly-associated protein, hyaluronan-mediated motility receptor, primase 1, erythropoietin, and neuregulin 1. In addition, pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then upregulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages. Conclusion: These findings provide a comprehensive molecular portrait of genomic changes in progressive HCV-related HCC. (HEPATOLOGY 2007;45:938-947.) Abbreviations: HCC, hepatocellular carcinoma; PAM, prediction analysis of microarray; qPCR, quantitative real-time reverse-transcriptase PCR; SAM, significance analysis of microarray.
Molecular Signatures Associated with HCV-Induced Hepatocellular Carcinoma and Liver Metastasis
PLoS ONE, 2013
Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV) infection represents the main cause of HCC. Using highdensity oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis.
Gene profiling of early and advanced liver disease in chronic hepatitis C patients
Hepatology international, 2011
Strong impact of hepatitis C virus (HCV) on normal regulation of cellular processes has been reported that could have significant implications for HCV pathogenesis. We aimed to determine the altered cellular processes during HCV infection with particular reference to advanced disease stages. Liver biopsy specimens of chronic hepatitis C patients classified on histological basis as early (fibrosis stage 1-2) or advanced (fibrosis stage 3-4) HCV disease were studied using microarray technology (Affymetrix GeneChip™ System). For comparison, liver specimens from patients with non-viral hepatitis (NV-hepatitis) were also analyzed by microarray. Expression data generated were analyzed using software Genespring GX and Ingenuity Pathway analysis to find the association with biological functions. We further validated the microarray results using quantitative reverse transcriptase-polymerase chain reaction. Data analysis through Genespring software revealed that in advanced HCV (A-HCV) a tota...