Abstract
BackgroundHepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. To identify distinct molecular mechanisms for early HCC we developed a rat model of liver regeneration post-hepatectomy, as well as liver cells undergoing malignant transformation and compared them to normal liver using a microarray approach. Subsequently, we performed cross-species comparative analysis coupled with copy number alterations (CNA) of independent early human HCC microarray studies to facilitate the identification of critical regulatory modules conserved across species.ResultsWe identified 35 signature genes conserved across species, and shared among different types of early human HCCs. Over 70% of signature genes were cancer-related, and more than 50% of the conserved genes were mapped to human genomic CNA regions. Functional annotation revealed genes already implicated in HCC, as well as novel genes which were not previously reported in liver tumors. A subset of differentially expressed genes was validated using quantitative RT-PCR. Concordance was also confirmed for a significant number of genes and pathways in five independent validation microarray datasets. Our results indicated alterations in a number of cancer related pathways, including p53, p38 MAPK, ERK/MAPK, PI3K/AKT, and TGF-β signaling pathways, and potential critical regulatory role of MYC, ERBB2, HNF4A, and SMAD3 for early HCC transformation.ConclusionsThe integrative analysis of transcriptional deregulation, genomic CNA and comparative cross species analysis brings new insights into the molecular profile of early hepatoma formation. This approach may lead to robust biomarkers for the detection of early human HCC.
Highlights
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths worldwide
Gene Expression Profiling Confirms Pathological Classification We performed genome-wide gene expression profiling of 24 samples for early HCC, regenerated liver and normal liver of both young and old rats using Applied Biosystems Rat Genome Survey microarray which includes more than 27,000 annotated genes from Celera and public repositories
To find genes that were differentially expressed across three different "treatment" types, and two age groups, we performed two-factor Analysis of Variance (ANOVA) to look for variations due to treatment, age and their interactions
Summary
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths worldwide. It is often diagnosed at an advanced stage, and typically has a poor prognosis. Developing animal models of HCC provide an experimental ground for dissecting the genetic and biological complexities of human cancer and contribute to our ability to identify and characterize pathogenic modifications relevant to early stages of cancer development and progression [18,19]. Combining cross-species comparative and/or functional genomics approaches with independent datasets from human and animal models of HCC along with genomic DNA copy number alterations enhances the ability to identify robust predictive markers for HCC [23,24,25,26]
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