Abstract
BackgroundUnderstanding hepatic zonation is important both for liver physiology and pathology. There is currently no effective systemic chemotherapy for human hepatocellular carcinoma (HCC) and its pathogenesis is of special interest. Genomic and proteomic data of HCC cells in different culture models, coupled to pathway-based analysis, can help identify HCC-related gene and pathway dysfunctions.ResultsWe identified zonation-related expression profiles contributing to selective phenotypes of HCC, by integrating relevant experimental observations through gene set enrichment analysis (GSEA). Analysis was based on gene and protein expression data measured on a human HCC cell line (HepG2/C3A) in two culture conditions: dynamic microfluidic biochips and static Petri dishes. Metabolic activity (HCC-related cytochromes P450) and genetic information processing were dominant in the dynamic cultures, in contrast to kinase signaling and cancer-specific profiles in static cultures. That, together with analysis of the published literature, leads us to propose that biochips culture conditions induce a periportal-like hepatocyte phenotype while standard plates cultures are more representative of a perivenous-like phenotype. Both proteomic data and GSEA results further reveal distinct ubiquitin-mediated protein regulation in the two culture conditions.ConclusionsPathways analysis, using gene and protein expression data from two cell culture models, confirmed specific human HCC phenotypes with regard to CYPs and kinases, and revealed a zonation-related pattern of expression. Ubiquitin-mediated regulation mechanism gives plausible explanations of our findings. Altogether, our results suggest that strategies aimed at inhibiting activated kinases and signaling pathways may lead to enhanced metabolism-mediated drug resistance of treated tumors. If that were the case, mitigating inhibition or targeting inactive forms of kinases would be an alternative.
Highlights
Understanding hepatic zonation is important both for liver physiology and pathology
Different categories of pathways are activated in μFB and Petri dishes (PD) We performed gene set enrichment analysis (GSEA) [16,17] of gene transcription and protein expression data obtained in human hepatocellular carcinoma (HCC) cell lines cultured in μFB and PD
A pronounced metabolism-pathways profile was found in μFB, while a signaling-pathways profile dominated in PD
Summary
Understanding hepatic zonation is important both for liver physiology and pathology. There is currently no effective systemic chemotherapy for human hepatocellular carcinoma (HCC) and its pathogenesis is of special interest. The functional unit of the liver, the lobule, is roughly cylindrical, with branches of the hepatic artery and portal vein together with bile ducts at its periphery, and a central vein branch in the middle Such a structure allows a natural distinction between upstream “periportal” and downstream “perivenous” hepatocytes, and constitutes the basis for “liver zonation”. Accumulating evidence indicates that WNT/b-catenin signaling plays a central role in the multi-level regulation of zonal gene expression in the liver [5]. It is implicated in several critical pathways responsible for initiating and maintaining dysregulated cell proliferation in HCC [9]. Understanding the relationships between the zonation of these pathways in the liver may deepen our views on the pathogenesis of HCC, its proliferation or maintenance
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