Genetic signatures shared in embryonic liver development and liver cancer define prognostically relevant subgroups in HCC

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.

[1]  F. Lemaigre.  Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. , 2009, Gastroenterology.

[2]  Michael Q. Zhang,et al.  Multi-stage analysis of gene expression and transcription regulation in C57/B6 mouse liver development. , 2009, Genomics.

[3]  C. Chuong,et al.  Morphogenesis of chicken liver: identification of localized growth zones and the role of beta-catenin/Wnt in size regulation. , 2004, Developmental biology.

[4]  J. Schwarzbauer,et al.  Temporal and spatial regulation of integrins during development. , 2008, Current opinion in cell biology.

[5]  P. Galle,et al.  Genome-wide analysis of factors regulating gene expression in liver. , 2007, Gene.

[6]  B. Cieply,et al.  β‐Catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development , 2008, Hepatology.

[7]  X. Wang,et al.  EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. , 2009, Gastroenterology.

[8]  Y. Ikeda,et al.  Prognosis of hepatocellular carcinoma with diabetes mellitus after hepatic resection , 1998, Hepatology.

[9]  F. Lemaigre.  Notch signaling in bile duct development: New insights raise new questions , 2008, Hepatology.

[10]  Hui Zhou,et al.  Liver‐enriched transcription factors regulate MicroRNA‐122 that targets CUTL1 during liver development , 2010, Hepatology.

[11]  Y. Ito,et al.  Retroviral gene transfer of signaling molecules into murine fetal hepatocytes defines distinct roles for the STAT3 and ras pathways during hepatic development , 2000, Hepatology.

[12]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[13]  V. Mazzaferro,et al.  Genome‐wide molecular profiles of HCV‐induced dysplasia and hepatocellular carcinoma , 2007, Hepatology.

[14]  G. Michalopoulos,et al.  Wnt impacts growth and differentiation in ex vivo liver development. , 2004, Experimental cell research.

[15]  M. Kanehisa.  A database for post-genome analysis. , 1997, Trends in genetics : TIG.

[16]  K. Kaestner,et al.  An FGF response pathway that mediates hepatic gene induction in embryonic endoderm cells. , 2006, Developmental cell.

[17]  Jessica Zucman-Rossi,et al.  Loss of Trim24 (Tif1α) gene function confers oncogenic activity to retinoic acid receptor alpha , 2007, Nature Genetics.

[18]  M Wang,et al.  Expression of Notch1, Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma. , 2009, Neoplasma.

[19]  S. Caldwell,et al.  The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology , 2009, Journal of Gastroenterology.

[20]  Richard M. Simon,et al.  Methods for assessing reproducibility of clustering patterns observed in analyses of microarray data , 2002, Bioinform..

[21]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[22]  A. Miyajima,et al.  Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. , 2009, Experimental cell research.

[23]  P. Courtoy,et al.  Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. , 2005, Genes & development.

[24]  Hans Clevers,et al.  Caught up in a Wnt storm: Wnt signaling in cancer. , 2003, Biochimica et biophysica acta.

[25]  S. Thorgeirsson,et al.  A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells , 2006, Nature Medicine.

[26]  A. Iwama,et al.  The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. , 2008, Cancer research.

[27]  G. Yeoh,et al.  Liver stem cells: A scientific and clinical perspective , 2008, Journal of gastroenterology and hepatology.

[28]  P. Galle,et al.  Collecting evidence for a stem cell hypothesis in HCC , 2010, Gut.

[29]  F. X. Bosch,et al.  Epidemiology of Primary Liver Cancer , 1999, Seminars in liver disease.

[30]  G. Michalopoulos,et al.  Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. , 2003, Gastroenterology.

[31]  W. Cheng,et al.  Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. , 2009, International journal of oncology.

[32]  T. Ichida,et al.  Impact of hepatitis B virus X protein on the DNA damage response during hepatocarcinogenesis , 2009, Medical Molecular Morphology.

[33]  Ken Matsumoto,et al.  Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium. , 2008, Developmental biology.

[34]  Jin Woo Kim,et al.  EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. , 2008, Cancer research.

[35]  Kenneth M. Yamada,et al.  The matrix reorganized: extracellular matrix remodeling and integrin signaling. , 2006, Current opinion in cell biology.

[36]  Xuegong Zhang,et al.  Comparison of gene expression in hepatocellular carcinoma, liver development, and liver regeneration , 2010, Molecular Genetics and Genomics.

[37]  S. Qiu,et al.  High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma , 2010, Gut.

[38]  N. Kato,et al.  Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. , 2008, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[39]  H. El‐Serag,et al.  Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. , 2004, Gastroenterology.

[40]  C. Deng,et al.  Smad Proteins and Hepatocyte Growth Factor Control Parallel Regulatory Pathways That Converge on β1-Integrin To Promote Normal Liver Development , 2001, Molecular and Cellular Biology.

[41]  Angela M. Liu,et al.  Gene Signatures Derived from a c-MET-Driven Liver Cancer Mouse Model Predict Survival of Patients with Hepatocellular Carcinoma , 2011, PloS one.

[42]  S. Dooley,et al.  Hypotheses on the Role of Transforming Growth Factor-β in the Onset and Progression of Hepatocellular Carcinoma , 2009, Digestive Diseases.

[43]  S. Thorgeirsson,et al.  Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling , 2004, Hepatology.