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Zonation related function and ubiquitination regulation in human hepatocellular carcinoma cells in dynamic vs. static culture conditions.

ABSTRACT: BACKGROUND: 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. 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. RESULTS: We 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. CONCLUSIONS: Pathways 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.

SUBMITTER: Cheng S

PROVIDER: S-EPMC3295679 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Zonation related function and ubiquitination regulation in human hepatocellular carcinoma cells in dynamic vs. static culture conditions.

Cheng Shu S Prot Jean-Matthieu JM Leclerc Eric E Bois Frédéric Y FY

BMC genomics 20120201

<h4>Background</h4>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. 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.<h4>Results</h4>We identified zonation-related expression profiles contributing to selective ...[more]

PMID: 22296956

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Project description:Abstract Background Hepatocellular carcinoma is one of the most lethal cancers worldwide. Novel prognostic and/or predictive biomarkers are urgently needed to improve patient management. Alpha‐fetoprotein (AFP) is a well‐established and widely used biomarker for hepatocellular carcinoma. However, diagnostic accuracy of static AFP values is limited and the clinical potential is a matter of ongoing scientific discussion. Objective We here evaluated the prognostic impact of pretreatment static and dynamic AFP variables on overall survival of hepatocellular carcinoma patients in a Western cohort. Methods Patients with confirmed hepatocellular carcinoma (n = 809) treated at the Johannes Gutenberg University Mainz between 1998 and 2014 and two available pretreatment AFP‐values (AFP‐slope) were retrospectively analysed. Clinicopathological baseline parameters, pretreatment static values and AFP‐slope were assessed. Prognostic impact was determined by Kaplan–Meier analyses and Cox regression models. Results High static and dynamic AFP variables prior to therapy were associated with reduced survival rates of hepatocellular carcinoma patients. Several known clinical parameters such as Child–Pugh B (p < 0.01) and C stage (p < 0.001), portal vein thrombosis (p < 0.001) and extrahepatic spread (p < 0.001) were confirmed as independent predictors for overall survival. Addition of static and/or dynamic AFP variable resulted in higher time‐dependent area under the curves. Notably, in patients with more favourable prognosis, AFP‐slope prior to therapy was a slightly stronger predictor for overall survival compared with static AFP values. Conclusion Static and dynamic AFP variables prior to therapy are predictive for overall survival of hepatocellular carcinoma patients. Addition of AFP‐slope to established prognostic parameters might improve prognostic classification for a subgroup of hepatocellular carcinoma patients with preserved liver function and without portal vein tumour thrombosis. Key Summary Alpha‐fetoprotein (AFP) is the most commonly used biomarker for hepatocellular carcinomas (HCCs), but accuracy of static and dynamic AFP values is limited and the prognostic significance is under debate. High static and dynamic AFP variables prior to therapy are associated with reduced survival rates of HCC patients across different tumour stages and treatment modalities. In patients with more favourable prognosis, AFP‐slope prior to therapy was a better predictor for overall survival in comparison with static AFP values. Addition of AFP‐slope to established prognostic parameters might improve prognostic classification for a subgroup of HCC.

Project description:BackgroundLiver zonation is a unique phenomenon in which the liver exhibits distinct functions among hepatocytes along the radial axis of the lobule. This phenomenon can cause the sectionalized initiation of several liver diseases, including hepatocellular carcinoma (HCC). However, few studies have explored the zonation features of HCC.MethodsFour single-cell RNA sequencing datasets were used to identify hepatocyte-specific zonation markers. Integrative analysis was then performed with a training RNA-seq cohort (616 HCC samples) and an external validating microarray cohort (285 HCC samples) from the International Cancer Genome Consortium, The Cancer Genome Atlas, Gene Expression Omnibus, and EMBL's European Bioinformatics Institute for clustering using non-negative matrix factorization consensus clustering based on zonation genes. Afterward, we evaluated the prognostic value, clinical characteristics, transcriptome and mutation features, immune infiltration, and immunotherapy response of the HCC subclasses.ResultsA total of 94 human hepatocyte-specific zonation markers (39 central markers and 55 portal markers) were identified for the first time. Subsequently, three subgroups of HCC, namely Cluster1, Cluster2, and Cluster3 were identified. Cluster1 exhibited a non-zonational-like signature with the worst prognosis. Cluster2 was intensively associated with a central-like signature and exhibited low immune infiltration and sensitivity toward immune blockade therapy. Cluster3 was intensively correlated with a portal-like signature with the best prognosis. Finally, we identified candidate therapeutic targets and agents for Cluster1 HCC samples.ConclusionThe current study established a novel HCC classification based on liver zonation signature. By classifying HCC into three clusters with non-zonational-like (Cluster1), central-like (Cluster2), and portal-like (Cluster3) features, this study provided new perspectives on the heterogeneity of HCC and shed new light on delivering precision medicine for HCC patients.

Dataset Information

Zonation related function and ubiquitination regulation in human hepatocellular carcinoma cells in dynamic vs. static culture conditions.

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Zonation related function and ubiquitination regulation in human hepatocellular carcinoma cells in dynamic vs. static culture conditions.

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