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

Cheng S, Prot JM, Leclerc E, Bois FY - BMC Genomics (2012)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Université de Technologie de Compiègne, BP 20529, 60205 Compiègne Cedex, France.

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.

Show MeSH

Related in: MedlinePlus

A joint subset of five genes, each of which participates in the overlapping four pathways in the PD group, constitutes the WNT signaling sub-pathway (CREBBP, MYC, PRKCG, PPP3CC and PPP3R2). These genes might constitute the specific induction of WNT signaling in HepG2/C3A cells (originating from an adolescent's liver).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3295679&req=5

Figure 1: A joint subset of five genes, each of which participates in the overlapping four pathways in the PD group, constitutes the WNT signaling sub-pathway (CREBBP, MYC, PRKCG, PPP3CC and PPP3R2). These genes might constitute the specific induction of WNT signaling in HepG2/C3A cells (originating from an adolescent's liver).

Mentions: To visualize β-catenin signaling expression in PD cultures, the KEGG WNT signaling pathway was drawn by Paintomics [35] on the basis of the PD gene expression data (Additional file 4, Figure S2). Over-expressed genes dominate the painted WNT signaling pathway, with dense connections between WNT signaling and the pathways governing focal adhesion, MAPK, TGF-β and calcium signaling pathways, all activated in PD cultures. Other relevant expressions in PD cultures are the nitrogen metabolism pathway, controlled by β-catenin [10], and the EGFR gene, which enhances β-catenin transcriptional activity [36]. Furthermore, five genes, each of which participates in the overlapping four pathways in PD cultures, are involved in the WNT signaling pathway (CREBBP, MYC, PRKCG, PPP3CC and PPP3R2) (Figure 1). These genes might constitute the specific induction of WNT signaling in HepG2/C3A cells (originating from an adolescent's liver) although MYC is normally not induced by β-catenin signaling in the adult liver [26]. The absence of CYPs in HepG2/C3A PD cultures is consistent with the overall repressive effect of Ras-Raf-MAPK signaling on expression of CYP enzymes [37].


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

Cheng S, Prot JM, Leclerc E, Bois FY - BMC Genomics (2012)

A joint subset of five genes, each of which participates in the overlapping four pathways in the PD group, constitutes the WNT signaling sub-pathway (CREBBP, MYC, PRKCG, PPP3CC and PPP3R2). These genes might constitute the specific induction of WNT signaling in HepG2/C3A cells (originating from an adolescent's liver).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3295679&req=5

Figure 1: A joint subset of five genes, each of which participates in the overlapping four pathways in the PD group, constitutes the WNT signaling sub-pathway (CREBBP, MYC, PRKCG, PPP3CC and PPP3R2). These genes might constitute the specific induction of WNT signaling in HepG2/C3A cells (originating from an adolescent's liver).
Mentions: To visualize β-catenin signaling expression in PD cultures, the KEGG WNT signaling pathway was drawn by Paintomics [35] on the basis of the PD gene expression data (Additional file 4, Figure S2). Over-expressed genes dominate the painted WNT signaling pathway, with dense connections between WNT signaling and the pathways governing focal adhesion, MAPK, TGF-β and calcium signaling pathways, all activated in PD cultures. Other relevant expressions in PD cultures are the nitrogen metabolism pathway, controlled by β-catenin [10], and the EGFR gene, which enhances β-catenin transcriptional activity [36]. Furthermore, five genes, each of which participates in the overlapping four pathways in PD cultures, are involved in the WNT signaling pathway (CREBBP, MYC, PRKCG, PPP3CC and PPP3R2) (Figure 1). These genes might constitute the specific induction of WNT signaling in HepG2/C3A cells (originating from an adolescent's liver) although MYC is normally not induced by β-catenin signaling in the adult liver [26]. The absence of CYPs in HepG2/C3A PD cultures is consistent with the overall repressive effect of Ras-Raf-MAPK signaling on expression of CYP enzymes [37].

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Université de Technologie de Compiègne, BP 20529, 60205 Compiègne Cedex, France.

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.

Show MeSH
Related in: MedlinePlus