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Published in: Irish Journal of Medical Science (1971 -) 2/2015

01-06-2015 | Original Article

Identifying hepatocellular carcinoma-related genes and pathways by system biology analysis

Authors: P. Wang, L. Ouyang, L. Zheng, Z. Wang

Published in: Irish Journal of Medical Science (1971 -) | Issue 2/2015

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Abstract

Background

Previous researches have been focused on revealing the functions of each individual gene and/or pathway in the initiation, progression and maintenance of hepatocellular carcinoma (HCC). However, the mechanistic relationships among different genes and/or pathways are largely unknown.

Aims

In this study, we tended to uncover the potential molecular networks and critical genes which play important roles in HCC progression.

Methods

The transcriptional profiles from normal and HCC patient samples were analyzed and compared using bioinformatic methods, including differentially expressed gene (DEG) analysis, hierarchical clustering, construction of protein–protein interaction (PPI) network and GO-Elite analysis.

Results

Initially, the normal and HCC sample data were processed and 679 most dramatic DEGs were identified. The PPI network analysis indicates the significance of multiple biological processes as well as signaling pathways in affecting liver function and HCC progression. In addition, hierarchical clustering analysis showed the most significant modules and identified the relationship between different genes, and some important genes such as FOS, IGF1, ADH4, ITGA2 and LEF1 were found to be hubs which master each individual module.

Conclusion

Our study greatly improves the understanding of the HCC development in a systematic manner and provides the potential clue for exploiting drugs which might target the most significant genes and/or signaling pathways.
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Literature
1.
go back to reference Adamek A, Kasprzak A, Mikos H et al (2013) The insulin-like growth factor-1 and expression of its binding protein-3 in chronic hepatitis C and hepatocellular carcinoma. Oncol Rep 30(3):1337–1345PubMed Adamek A, Kasprzak A, Mikos H et al (2013) The insulin-like growth factor-1 and expression of its binding protein-3 in chronic hepatitis C and hepatocellular carcinoma. Oncol Rep 30(3):1337–1345PubMed
2.
go back to reference American Cancer Society (2013) Cancer Statistics 2013, 1–59 American Cancer Society (2013) Cancer Statistics 2013, 1–59
3.
go back to reference Asselah T, Bieche I, Laurendeau I et al (2005) Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C. Gastroenterology 129:2064–2075CrossRefPubMed Asselah T, Bieche I, Laurendeau I et al (2005) Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C. Gastroenterology 129:2064–2075CrossRefPubMed
4.
go back to reference Bevoglu D, Imbeaud S, Maurhofer O et al (2013) Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification. Hepatology 58:229–238CrossRef Bevoglu D, Imbeaud S, Maurhofer O et al (2013) Tissue metabolomics of hepatocellular carcinoma: tumor energy metabolism and the role of transcriptomic classification. Hepatology 58:229–238CrossRef
5.
go back to reference Boyault S, Rickman DS, de Reynies A et al (2007) Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45:42–52CrossRefPubMed Boyault S, Rickman DS, de Reynies A et al (2007) Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45:42–52CrossRefPubMed
6.
go back to reference Chaudhary P, Sharma R, Sahu M et al (2013) 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. J Biol Chem 288:20532–20546CrossRefPubMedCentralPubMed Chaudhary P, Sharma R, Sahu M et al (2013) 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. J Biol Chem 288:20532–20546CrossRefPubMedCentralPubMed
7.
go back to reference Coutts AS, La Thangue N (2006) The p53 response during DNA damage: impact of transcriptional cofactors. BioChem Soc Symp 73:181–189PubMed Coutts AS, La Thangue N (2006) The p53 response during DNA damage: impact of transcriptional cofactors. BioChem Soc Symp 73:181–189PubMed
8.
go back to reference Drozoy I, Bornschein J, Wex T et al (2012) Functional and topological properties in hepatocellular carcinoma transcriptome. PLoS ONE 7:e35510CrossRef Drozoy I, Bornschein J, Wex T et al (2012) Functional and topological properties in hepatocellular carcinoma transcriptome. PLoS ONE 7:e35510CrossRef
9.
go back to reference Dihal AA, van der Woude H et al (2008) Transcriptome and proteome profiling of colon mucosa from quercetin fed F344 rats point to tumor preventive mechanisms, increased mitochondrial fatty acid degradation and decreased glycolysis. Proteomics 8(1):45–61CrossRefPubMed Dihal AA, van der Woude H et al (2008) Transcriptome and proteome profiling of colon mucosa from quercetin fed F344 rats point to tumor preventive mechanisms, increased mitochondrial fatty acid degradation and decreased glycolysis. Proteomics 8(1):45–61CrossRefPubMed
11.
go back to reference Han YC, Zheng ZL et al (2013) Metallothionein 1 h tumour suppressor activity in prostate cancer is mediated by euchromatin methyltransferase 1. J Pathol 230(2):184–193CrossRefPubMedCentralPubMed Han YC, Zheng ZL et al (2013) Metallothionein 1 h tumour suppressor activity in prostate cancer is mediated by euchromatin methyltransferase 1. J Pathol 230(2):184–193CrossRefPubMedCentralPubMed
12.
go back to reference Halaby MJ, Yang DQ (2007) p53 translational control: a new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics. Gene 395:1–7CrossRefPubMed Halaby MJ, Yang DQ (2007) p53 translational control: a new facet of p53 regulation and its implication for tumorigenesis and cancer therapeutics. Gene 395:1–7CrossRefPubMed
13.
go back to reference Hayashi M, Nomoto S et al (2014) Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma. BMC Cancer 14(1):108CrossRefPubMedCentralPubMed Hayashi M, Nomoto S et al (2014) Identification of the collagen type 1 alpha 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma. BMC Cancer 14(1):108CrossRefPubMedCentralPubMed
14.
go back to reference Huang C, Wang Y et al (2013) Quantitative proteomic analysis identified paraoxonase 1 as a novel serum biomarker for microvascular invasion in hepatocellular carcinoma. J Proteome Res 12(4):1838–1846CrossRefPubMed Huang C, Wang Y et al (2013) Quantitative proteomic analysis identified paraoxonase 1 as a novel serum biomarker for microvascular invasion in hepatocellular carcinoma. J Proteome Res 12(4):1838–1846CrossRefPubMed
15.
go back to reference Jiang J, Gusev Y, Aderca I et al (2008) Association of Micro RNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 14:419–427CrossRefPubMedCentralPubMed Jiang J, Gusev Y, Aderca I et al (2008) Association of Micro RNA expression in hepatocellular carcinomas with hepatitis infection, cirrhosis, and patient survival. Clin Cancer Res 14:419–427CrossRefPubMedCentralPubMed
16.
go back to reference Jiang JG, Chen CL, Card JW et al (2005) Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res 65:4707–4715CrossRefPubMed Jiang JG, Chen CL, Card JW et al (2005) Cytochrome P450 2J2 promotes the neoplastic phenotype of carcinoma cells and is up-regulated in human tumors. Cancer Res 65:4707–4715CrossRefPubMed
17.
go back to reference Kao YH, Chen CL, Jawan B et al (2010) Upregulation of hepatoma-derived growth factor is involved in murine hepatic fibrogenesis. J Hepatol 52(1):96–105CrossRefPubMed Kao YH, Chen CL, Jawan B et al (2010) Upregulation of hepatoma-derived growth factor is involved in murine hepatic fibrogenesis. J Hepatol 52(1):96–105CrossRefPubMed
19.
go back to reference Lai KK, Shang S, Lohia N et al (2011) Extracellular matrix dynamics in hepatocarcinogenesis: a comparative proteomics study of PDGFC transgenic and Pten null mouse models. PLoS Genet 7:e1002147CrossRefPubMedCentralPubMed Lai KK, Shang S, Lohia N et al (2011) Extracellular matrix dynamics in hepatocarcinogenesis: a comparative proteomics study of PDGFC transgenic and Pten null mouse models. PLoS Genet 7:e1002147CrossRefPubMedCentralPubMed
20.
go back to reference Lee SY, Kim JW et al (2008) Microtubule-associated protein 1B light chain (MAP1B-LC1) negatively regulates the activity of tumor suppressor p53 in neuroblastoma cells. FEBS Lett 582(19):2826–2832CrossRefPubMed Lee SY, Kim JW et al (2008) Microtubule-associated protein 1B light chain (MAP1B-LC1) negatively regulates the activity of tumor suppressor p53 in neuroblastoma cells. FEBS Lett 582(19):2826–2832CrossRefPubMed
21.
go back to reference Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330:1340–1344CrossRefPubMed Levine AJ, Puzio-Kuter AM (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330:1340–1344CrossRefPubMed
22.
go back to reference Matsuo M, Terai K et al (2012) Designation of enzyme activity of glycine-N-acyltransferase family genes and depression of glycine-N-acyltransferase in human hepatocellular carcinoma. Biochem Biophys Res Commun 420(4):901–906CrossRefPubMed Matsuo M, Terai K et al (2012) Designation of enzyme activity of glycine-N-acyltransferase family genes and depression of glycine-N-acyltransferase in human hepatocellular carcinoma. Biochem Biophys Res Commun 420(4):901–906CrossRefPubMed
23.
go back to reference Mazurek S (2011) Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 43:969–980CrossRefPubMed Mazurek S (2011) Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 43:969–980CrossRefPubMed
24.
go back to reference Midorikawa Y, Makuuchi M, Tang W et al (2007) Microarray-based analysis for hepatocellular carcinoma: from gene expression profiling to new challenges. World J Gastroenterol 13:1487–1492CrossRefPubMedCentralPubMed Midorikawa Y, Makuuchi M, Tang W et al (2007) Microarray-based analysis for hepatocellular carcinoma: from gene expression profiling to new challenges. World J Gastroenterol 13:1487–1492CrossRefPubMedCentralPubMed
25.
go back to reference Oh JH, Kim YB, Gurnani P et al (2008) Biomarker selection and sample prediction for multi-category disease on MALDI-TOF data. Bioinformatics 24:1812–1818CrossRefPubMed Oh JH, Kim YB, Gurnani P et al (2008) Biomarker selection and sample prediction for multi-category disease on MALDI-TOF data. Bioinformatics 24:1812–1818CrossRefPubMed
26.
go back to reference Pei Y, Zhang T, Renault V et al (2009) An overview of hepatocellular carcinoma study by omics-based methods. Acta Biochim Biophys Sin (Shanghai) 41:1–15CrossRef Pei Y, Zhang T, Renault V et al (2009) An overview of hepatocellular carcinoma study by omics-based methods. Acta Biochim Biophys Sin (Shanghai) 41:1–15CrossRef
27.
go back to reference Rehem RN, El-Shikh WM (2011) Serum IGF-1, IGF-2 and IGFBP-3 as parameters in the assessment of liver dysfunction in patients with hepatic cirrhosis and in the diagnosis of hepatocellular carcinoma. Hepatogastroenterology 58:949–954PubMed Rehem RN, El-Shikh WM (2011) Serum IGF-1, IGF-2 and IGFBP-3 as parameters in the assessment of liver dysfunction in patients with hepatic cirrhosis and in the diagnosis of hepatocellular carcinoma. Hepatogastroenterology 58:949–954PubMed
28.
go back to reference Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W (eds) Bioinformatics and computational biology solutions using R and bioconductor. Springer, New York, pp 397–420 Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W (eds) Bioinformatics and computational biology solutions using R and bioconductor. Springer, New York, pp 397–420
29.
go back to reference Sun S, Lee NP, Poon RT et al (2007) Oncoproteomics of hepatocellular carcinoma: from cancer markers’ discovery to functional pathways. Liver Int 27:1021–1038CrossRefPubMed Sun S, Lee NP, Poon RT et al (2007) Oncoproteomics of hepatocellular carcinoma: from cancer markers’ discovery to functional pathways. Liver Int 27:1021–1038CrossRefPubMed
30.
go back to reference Szklarczyk D, Franceschini A, Kuhn M et al (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39:D561–D568CrossRefPubMedCentralPubMed Szklarczyk D, Franceschini A, Kuhn M et al (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39:D561–D568CrossRefPubMedCentralPubMed
31.
go back to reference Tanaka S, Moqushi K, Yasen M et al (2011) Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: a prospective, multicenter study. Hepatology 54:1273–1281CrossRefPubMed Tanaka S, Moqushi K, Yasen M et al (2011) Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: a prospective, multicenter study. Hepatology 54:1273–1281CrossRefPubMed
32.
go back to reference Taniquchi K, Yamada T, Sasaki Y et al (2010) Genetic and epigenetic characteristics of human multiple hepatocellular carcinoma. BMC Cancer 10:530CrossRef Taniquchi K, Yamada T, Sasaki Y et al (2010) Genetic and epigenetic characteristics of human multiple hepatocellular carcinoma. BMC Cancer 10:530CrossRef
33.
go back to reference Tavazoie S, Huqhes JD, Campbell MJ et al (1999) Systematic determination of genetic network architecture. Nat Genet 22:281–285CrossRefPubMed Tavazoie S, Huqhes JD, Campbell MJ et al (1999) Systematic determination of genetic network architecture. Nat Genet 22:281–285CrossRefPubMed
34.
go back to reference Troyanskaya O, Cantor M, Sherlock G et al (2001) Missing value estimation methods for DNA microarrays. Bioinformatics 17:520–525CrossRefPubMed Troyanskaya O, Cantor M, Sherlock G et al (2001) Missing value estimation methods for DNA microarrays. Bioinformatics 17:520–525CrossRefPubMed
35.
go back to reference Wang L, Huang J, Jiang M (2010) RRM2 computational phosphoprotein network construction and analysis between no-tumor hepatitis/cirrhotic liver tissues and human hepatocellular carcinoma (HCC). Cell Physiol Biochem 26:303–310CrossRefPubMed Wang L, Huang J, Jiang M (2010) RRM2 computational phosphoprotein network construction and analysis between no-tumor hepatitis/cirrhotic liver tissues and human hepatocellular carcinoma (HCC). Cell Physiol Biochem 26:303–310CrossRefPubMed
36.
go back to reference Wang W, Sun Q, Wu Z et al (2013) Mitochondrial dysfunction-related genes in hepatocellular carcinoma. Front Biosci (Landmark Ed) 18:1141–1149CrossRef Wang W, Sun Q, Wu Z et al (2013) Mitochondrial dysfunction-related genes in hepatocellular carcinoma. Front Biosci (Landmark Ed) 18:1141–1149CrossRef
37.
go back to reference Wang Z, Jiang Y, Guan D et al (2013) Critical roles of p53 in epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma cells. PLoS ONE 8:e72486CrossRefPubMedCentralPubMed Wang Z, Jiang Y, Guan D et al (2013) Critical roles of p53 in epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma cells. PLoS ONE 8:e72486CrossRefPubMedCentralPubMed
38.
go back to reference Wei RR, Zhang MY, Rao HL et al (2012) Identification of ADH4 as a novel and potential prognostic marker in hepatocellular carcinoma. Med Oncol 29:2737–2743CrossRefPubMed Wei RR, Zhang MY, Rao HL et al (2012) Identification of ADH4 as a novel and potential prognostic marker in hepatocellular carcinoma. Med Oncol 29:2737–2743CrossRefPubMed
39.
go back to reference Wu Z, Irizarry RA, Gentleman R et al (2004) A model-based background adjustment for oligonucleotide expression arrays. J Am Stat Assoc 99:909–917CrossRef Wu Z, Irizarry RA, Gentleman R et al (2004) A model-based background adjustment for oligonucleotide expression arrays. J Am Stat Assoc 99:909–917CrossRef
40.
go back to reference Wurmbach E, Chen YB, Khitroy G et al (2007) Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45:938–947CrossRefPubMed Wurmbach E, Chen YB, Khitroy G et al (2007) Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 45:938–947CrossRefPubMed
42.
43.
go back to reference Zhang X, Lu X, Shi Q et al (2006) Recursive SVM feature selection and sample classification for mass-spectrometry and microarray data. BMC Bioinformatics 7:197CrossRefPubMedCentralPubMed Zhang X, Lu X, Shi Q et al (2006) Recursive SVM feature selection and sample classification for mass-spectrometry and microarray data. BMC Bioinformatics 7:197CrossRefPubMedCentralPubMed
45.
go back to reference Zhou HJ, Liu YK, Li Z et al (2007) Analysing protein–protein interaction networks of human liver cancer cell lines with diverse metastasis potential. J Cancer Res Clin Oncol 133:663–672CrossRefPubMed Zhou HJ, Liu YK, Li Z et al (2007) Analysing protein–protein interaction networks of human liver cancer cell lines with diverse metastasis potential. J Cancer Res Clin Oncol 133:663–672CrossRefPubMed
46.
go back to reference Zhou SF, Wang B, Yang LP et al (2010) Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 42:268–354CrossRefPubMed Zhou SF, Wang B, Yang LP et al (2010) Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 42:268–354CrossRefPubMed
Metadata
Title
Identifying hepatocellular carcinoma-related genes and pathways by system biology analysis
Authors
P. Wang
L. Ouyang
L. Zheng
Z. Wang
Publication date
01-06-2015
Publisher
Springer London
Published in
Irish Journal of Medical Science (1971 -) / Issue 2/2015
Print ISSN: 0021-1265
Electronic ISSN: 1863-4362
DOI
https://doi.org/10.1007/s11845-014-1119-y

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