Genetic Signatures Shared in Embryonic Liver Development and Liver Cancer Define Prognostically Relevant Subgroups in HCC

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2012 Aug 16

PMID 22891627

Citations 19

Authors

Diana Becker

Ioannis Sfakianakis

Markus Krupp

Frank Staib

Aslihan Gerhold-Ay

Anja Victor

Harald Binder

Maria Blettner

Thorsten Maass

Snorri Thorgeirsson

Peter R Galle

Andreas Teufel

Affiliations

Soon will be listed here.

Abstract

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.

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References

Li T, Huang J, Jiang Y, Zeng Y, He F, Zhang M . Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development. Genomics. 2008; 93(3):235-42. PMC: 2995988. DOI: 10.1016/j.ygeno.2008.10.006. View

Lee J, Chu I, Heo J, Calvisi D, Sun Z, Roskams T . Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004; 40(3):667-76. DOI: 10.1002/hep.20375. View

Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang H . EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009; 136(3):1012-24. PMC: 2828822. DOI: 10.1053/j.gastro.2008.12.004. View

Irizarry R, Hobbs B, Collin F, Beazer-Barclay Y, Antonellis K, Scherf U . Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003; 4(2):249-64. DOI: 10.1093/biostatistics/4.2.249. View

Teufel A, Weinmann A, Krupp M, Budinger M, Galle P . Genome-wide analysis of factors regulating gene expression in liver. Gene. 2006; 389(2):114-21. DOI: 10.1016/j.gene.2006.10.021. View

Dooley S, Weng H, Mertens P . Hypotheses on the role of transforming growth factor-beta in the onset and progression of hepatocellular carcinoma. Dig Dis. 2009; 27(2):93-101. DOI: 10.1159/000218340. View

Suksaweang S, Lin C, Jiang T, Hughes M, Widelitz R, Chuong C . Morphogenesis of chicken liver: identification of localized growth zones and the role of beta-catenin/Wnt in size regulation. Dev Biol. 2004; 266(1):109-22. PMC: 4376314. DOI: 10.1016/j.ydbio.2003.10.010. View

Dan Y, Yeoh G . Liver stem cells: a scientific and clinical perspective. J Gastroenterol Hepatol. 2008; 23(5):687-98. DOI: 10.1111/j.1440-1746.2008.05383.x. View

Xu H, He J, Xiao Z, Zhang Q, Chen Y, Zhou H . Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development. Hepatology. 2010; 52(4):1431-42. DOI: 10.1002/hep.23818. View

10.

Chiba T, Miyagi S, Saraya A, Aoki R, Seki A, Morita Y . The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res. 2008; 68(19):7742-9. DOI: 10.1158/0008-5472.CAN-07-5882. View

11.

Khetchoumian K, Teletin M, Tisserand J, Mark M, Herquel B, Ignat M . Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha. Nat Genet. 2007; 39(12):1500-6. DOI: 10.1038/ng.2007.15. View

12.

Wang M, Xue L, Cao Q, Lin Y, Ding Y, Yang P . Expression of Notch1, Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma. Neoplasma. 2009; 56(6):533-41. DOI: 10.4149/neo_2009_06_533. View

13.

Li T, Wan B, Huang J, Zhang X . Comparison of gene expression in hepatocellular carcinoma, liver development, and liver regeneration. Mol Genet Genomics. 2010; 283(5):485-92. DOI: 10.1007/s00438-010-0530-y. View

14.

Lemaigre F . Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology. 2009; 137(1):62-79. DOI: 10.1053/j.gastro.2009.03.035. View

15.

Ito Y, Matsui T, Kamiya A, Kinoshita T, Miyajima A . Retroviral gene transfer of signaling molecules into murine fetal hepatocytes defines distinct roles for the STAT3 and ras pathways during hepatic development. Hepatology. 2000; 32(6):1370-6. DOI: 10.1053/jhep.2000.19815. View

16.

Calmont A, Wandzioch E, Tremblay K, Minowada G, Kaestner K, Martin G . An FGF response pathway that mediates hepatic gene induction in embryonic endoderm cells. Dev Cell. 2006; 11(3):339-48. DOI: 10.1016/j.devcel.2006.06.015. View

17.

Larsen M, Artym V, Green J, Yamada K . The matrix reorganized: extracellular matrix remodeling and integrin signaling. Curr Opin Cell Biol. 2006; 18(5):463-71. DOI: 10.1016/j.ceb.2006.08.009. View

18.

El-Serag H, Tran T, Everhart J . Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology. 2004; 126(2):460-8. DOI: 10.1053/j.gastro.2003.10.065. View

19.

Meighan C, Schwarzbauer J . Temporal and spatial regulation of integrins during development. Curr Opin Cell Biol. 2008; 20(5):520-4. PMC: 2572561. DOI: 10.1016/j.ceb.2008.05.010. View

20.

Ikeda Y, Shimada M, Hasegawa H, Gion T, Kajiyama K, Shirabe K . Prognosis of hepatocellular carcinoma with diabetes mellitus after hepatic resection. Hepatology. 1998; 27(6):1567-71. DOI: 10.1002/hep.510270615. View