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Distinct expression patterns in hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma.

ABSTRACT: AIM:To identify biomarkers indicating virus-specific hepatocarcinogenic process, differential mRNA expression in 32 patients with hepatitis B virus (HBV)-/hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) were investigated by means of cDNA microarrays comprising of 886 genes. METHODS:Thirty two HCC patients were divided into two groups based on viral markers: hepatitis B virus positive and HCV positive. The expression profiles of 32 pairs of specimens (tumorous and surrounding non-tumorous liver tissues), consisting of 886 genes were analyzed. RESULTS:Seven up-regulated genes in HBV-associated HCC comprised genes involved in protein synthesis (RPS5), cytoskeletal organization (KRT8), apoptosis related genes (CFLAR), transport (ATP5F1), cell membrane receptor related genes (IGFBP2), signal transduction or transcription related genes (MAP3K5), and metastasis-related genes (MMP9). The up-regulated genes in HCV-infected group included 4 genes: VIM (cell structure), ACTB (cell structure), GAPD (glycolysis) and CD58 (cell adhesion). The expression patterns of the 11 genes, identified by cDNA microarray, were confirmed by quantitative RT-PCR in 32 specimens. CONCLUSION:The patterns of all identified genes were classified based on the viral factor involved in HBV- and HCV-associated HCC. Our results strongly suggest that the pattern of gene expression in HCC is closely associated with the etiologic factor. The present study indicates that HBV and HCV cause hepatocarcinogenesis by different mechanisms, and provide novel tools for the diagnosis and treatment of HBV- and HCV-associated HCC.

SUBMITTER: Lee CF

PROVIDER: S-EPMC2760187 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Distinct expression patterns in hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma.

Lee Chun-Feng CF Ling Zhi-Qiang ZQ Zhao Ting T Lee Kuan-Rong KR

World journal of gastroenterology 20081001 39

<h4>Aim</h4>To identify biomarkers indicating virus-specific hepatocarcinogenic process, differential mRNA expression in 32 patients with hepatitis B virus (HBV)-/hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) were investigated by means of cDNA microarrays comprising of 886 genes.<h4>Methods</h4>Thirty two HCC patients were divided into two groups based on viral markers: hepatitis B virus positive and HCV positive. The expression profiles of 32 pairs of specimens (tumorous and ...[more]

PMID: 18932288

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Project description:Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) initiation and is associated with worse outcomes. Many prior studies of HBV-related HCC have not accounted for potential heterogeneity among HBV-related tumors by assessing whether HBV activity is present in tumor tissue. Here, we measured tumor HBV RNA, a proxy for viral activity, and investigated the association between HBV RNA status and several clinicogenomic characteristics. We obtained clinical, mutation, RNA-Seq and survival data for 439 HCC tumors from The Cancer Genome Atlas and International Cancer Genome Consortium. Tumors were classified as HBV RNA positive if they harbored >1 HBV RNA read per million human reads. We investigated the association between HBV RNA status and nonsynonymous somatic mutations, gene set expression, homologous recombination deficiency (HRD) score and mutation-specific survival. HBV RNA positive status was associated with higher nonsynonymous mutation rates of multiple genes, including TP53 and CDKN2A, while HBV RNA negative status was associated with higher nonsynonymous BAP1 mutation rate. HBV RNA positive status was also associated with increased transcription of genes involved in multiple DNA damage repair pathways, genes upregulated by MYC and mTORC1, and genes overexpressed in several HCC subclasses associated with a proliferative phenotype. Further, HBV RNA positive status was associated with increased three-biomarker HRD score (22.2 for HBV RNA+ vs. 16.0 for HBV RNA-). Finally, HBV RNA status was associated with multiple mutation-specific survival differences, including decreased survival for HBV RNA positive patients with nonsynonymous KEAP1 mutations compared to those without (hazard ratio 4.26). HCC tumors harboring genomic evidence of HBV activity therefore constitute a distinct HCC subset characterized by specific differences in nonsynonymous mutations, gene set expression, three-biomarker HRD score and mutation-specific survival.

Project description:Hepatitis B virus (HBV) is a major cause of liver diseases, including hepatocellular carcinoma (HCC), and more than 650,000 people die annually due to HBV-associated liver failure. Extensive studies of individual promoters have revealed that heterogeneous RNA 5' ends contribute to the complexity of HBV transcriptome and proteome. Here, we provide a comprehensive map of HBV transcription start sites (TSSs) in human liver, HCC, and blood, as well as several experimental replication systems, at a single-nucleotide resolution. Using CAGE (cap analysis of gene expression) analysis of 16 HCC/nontumor liver pairs, we identify 17 robust TSSs, including a novel promoter for the X gene located in the middle of the gene body, which potentially produces a shorter X protein translated from the conserved second start codon, and two minor antisense transcripts that might represent viral noncoding RNAs. Interestingly, transcription profiles were similar in HCC and nontumor livers, although quantitative analysis revealed highly variable patterns of TSS usage among clinical samples, reflecting precise regulation of HBV transcription initiation at each promoter. Unlike the variety of TSSs found in liver and HCC, the vast majority of transcripts detected in HBV-positive blood samples are pregenomic RNA, most likely generated and released from liver. Our quantitative TSS mapping using the CAGE technology will allow better understanding of HBV transcriptional responses in further studies aimed at eradicating HBV in chronic carriers.Despite the availability of a safe and effective vaccine, HBV infection remains a global health problem, and current antiviral protocols are not able to eliminate the virus in chronic carriers. Previous studies of the regulation of HBV transcription have described four major promoters and two enhancers, but little is known about their activity in human livers and HCC. We deeply sequenced the HBV RNA 5' ends in clinical human samples and experimental models by using a new, sensitive and quantitative method termed cap analysis of gene expression (CAGE). Our data provide the first comprehensive map of global TSS distribution over the entire HBV genome in the human liver, validating already known promoters and identifying novel locations. Better knowledge of HBV transcriptional activity in the clinical setting has critical implications in the evaluation of therapeutic approaches that target HBV replication.

Project description:Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored. Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied. Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues (r = 0.72, p = 1.6e-45). Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster (Chi-square: 16.86, P = 0.0002). Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024). Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue.

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Distinct expression patterns in hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma.

Publications

Distinct expression patterns in hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma.

Similar Datasets

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