The online version of this article (doi:10.1186/1476-4598-11-55) contains supplementary material, which is available to authorized users.
The authors declare no conflict of interest.
DB designed the study, carried out the data analysis, manuscript preparation. IS carried out the data analysis. MK carried out the data analysis. FS carried out the data analysis. AGA carried out the data analysis and statistical evaluation. AV carried out the statistical evaluation. HB carried out the statistical evaluation. MB carried out the statistical evaluation. TM carried out the data analysis. ST carried out the data generation and participated in the manuscript proof reading. PRG participated in the data discussion and manuscript preparation. AT designed the study, carried out data analysis, and manuscript preparation. All authors read and approved the final manuscript.
Multiple activations of individual genes during embryonic liver and HCC development have repeatedly prompted speculations about conserved embryonic signatures driving cancer development. Recently, the emerging discussion on cancer stem cells and the appreciation that generally tumors may develop from progenitor cells of diverse stages of cellular differentiation has shed increasing light on the overlapping genetic signatures between embryonic liver development and HCC. However there is still a lack of systematic studies investigating this area. We therefore performed a comprehensive analysis of differentially regulated genetic signaling pathways in embryonic and liver cancer development and investigated their biological relevance.
Genetic signaling pathways were investigated on several publically available genome wide microarray experiments on liver development and HCC. Differentially expressed genes were investigated for pathway enrichment or underrepresentation compared to KEGG annotated pathways by Fisher exact evaluation. The comparative analysis of enrichment and under representation of differentially regulated genes in liver development and HCC demonstrated a significant overlap between multiple pathways. Most strikingly we demonstrated a significant overlap not only in pathways expected to be relevant to both conditions such as cell cycle or apoptosis but also metabolic pathways associated with carbohydrate and lipid metabolism. Furthermore, we demonstrated the clinical significance of these findings as unsupervised clustering of HCC patients on the basis of these metabolic pathways displayed significant differences in survival.
These results indicate that liver development and liver cancer share similar alterations in multiple genetic signaling pathways. Several pathways with markedly similar patterns of enrichment or underrepresentation of various regulated genes between liver development and HCC are of prognostic relevance in HCC. In particular, the metabolic pathways were identified as novel prognostically relevant players in HCC development.
Additional file 1: Table S7. KEGG Pathway Analysis on a second human HCC of Microarray-Set GSE25097[ 33]. Each grey square at the grid intersection between pathway and developmental stage represents a significant enrichment (black circuits) or under re-presentation (white circuits) of differentially regulated genes of this pathway in the analyzed data set. (JPEG 532 KB)
Additional file 2: Table S1. Intersection of Genes within Pathways between human HCC Liver samples and mouse samples (GSE13149, murine HCC: Trim24 knockout mice and Mdr2 knockout mice) for the pathway category “Carbohydrate Metabolism”. Table S2: Intersection of Genes within Pathways between human HCC Liver samples and mouse samples (GSE13149, murine HCC: Trim24 knockout mice and Mdr2 knockout mice) for the pathway category “Lipid Metabolism”. Table S3: Intersection of Genes within Pathways between human HCC Liver samples and mouse samples (GSE13149, murine HCC: Trim24 knockout mice and Mdr2 knockout mice) for the pathway category “Cell Growth and Death”. Table S4: Intersection of Genes within Pathways between human HCC Liver samples and mouse samples (GSE13149, murine HCC: Trim24 knockout mice and Mdr2 knockout mice) for the pathway category “Signaling Molecules and Interaction”. Table S5: P-value and observed/expected ratio range for each Pathway. Table S6: Genes used for survival calculation. (DOC 140 KB)12943_2012_1069_MOESM2_ESM.doc
Additional file 3: Figure S8. Corresponding heatmaps to the Kaplan Meier estimated survival (Figures 2, 3, 4, 5). (JPEG 1 MB)
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- Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC
Peter R Galle
- BioMed Central
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