Integrative and comparative genomics analysis of early hepatocellular carcinoma differentiated from liver regeneration in young and old

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.

Molecular Genetics and Genomics of Hepatocellular Carcinoma

“…Each model appears to have its own advantages and disadvantages [100]. Recent studies, including our own, demonstrated the usefulness of modeling human cancer in diethylnitrosamine (DEN)-induced in rats [54] as well as in genetically engineered mice [97,101].…”

“…The studies using integrative analysis of genomic aberrations with the expression profiling demonstrated the usefulness of this approach to identify the likely drivers of cancer [105] and helped better understand the processes affected by the drivers/passenger factors and led to obtain novel insights into pathobiology of HCC [17,54,105].…”

“…In this context, we performed cross-species and integrative genomic analysis to identify potential biomarker genes for early HCC [54]. In this study, we first developed a rat model of early HCC as well as liver regeneration post-hepatectomy and compared them to normal liver using a microarray approach.…”

“…The recent studies have used cross-species comparative genomics approach, that identifies genes that are conserved in animal models of cancer and in human cancer, that would facilitate the identification of critical regulatory modules conserved across species in the expression profiles and to understand the molecular pathogenesis of various cancers, including HCC [36,54,[101][102][103]. The cross-species comparative analysis of animal models and human HCCs would provide new therapeutic strategies to maximize the efficiency of treatments.…”

“…Recently considerable attention has been placed on global gene expression studies as well as genomic aberrations in order to understand the pathogenesis of HCC, and to look for possible early markers of detection [14, 16-17, 28, 34, 49-51]. Furthermore, combining crossspecies comparative and/or functional genomics approaches from human and animal models of HCC along with genomic DNA copy number alterations enhances the ability to identify robust predictive markers for HCC [13,36,[52][53][54]. Thus, characterization of diverse HCC subgroups using the array technologies together with improved analytical approaches are crucial for better management of the disease, especially in the era of personalized medicine approach in HCC treatment.…”