Protein-protein interaction analysis to identify biomarker networks for endometriosis

The identification of biomarkers and their interaction network involved in the processes of endometriosis is a critical step in understanding the underlying mechanisms of the disease. The aim of the present study was to construct biomarker networks of endometriosis that integrated human protein-protein interactions and known disease-causing genes. Endometriosis-associated genes were extracted from Genotator and DisGeNet and biomarker network and pathway analyses were constructed using atBioNet. Of 100 input genes, 96 were strongly mapped to six major modules. The majority of the pathways in the first module were associated with the proliferation of cancer cells, the enriched pathways in module B were associated with the immune system and infectious diseases, module C included pathways related to immune and metastasis, the enriched pathways in module D were associated with inflammatory processes, and the majority of the pathways in module E were related to replication and repair. The present approach identified known and potential biomarkers in endometriosis. The identified biomarker networks are highly enriched in biological pathways associated with endometriosis, which may provide further insight into the molecular mechanisms underlying endometriosis.

[1]  Tao Wang,et al.  Identification of biomarkers for endometriosis in eutopic endometrial cells from patients with endometriosis using a proteomics approach. , 2013, Molecular medicine reports.

[2]  U. Kayisli,et al.  Extracellular Matrix-Dependent Regulation of Fas Ligand Expression in Human Endometrial Stromal Cells , 2002, Biology of reproduction.

[3]  中尾 光輝,et al.  KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース) , 2000 .

[4]  Himanshu Kumar,et al.  Toll-like receptors and innate immunity. , 2009, Biochemical and biophysical research communications.

[5]  K. Becker,et al.  The Genetic Association Database , 2004, Nature Genetics.

[6]  Sandhya Rani,et al.  Human Protein Reference Database—2009 update , 2008, Nucleic Acids Res..

[7]  Peilin Jia,et al.  A comprehensive network and pathway analysis of candidate genes in major depressive disorder , 2011, BMC Systems Biology.

[8]  A. Barabasi,et al.  Interactome Networks and Human Disease , 2011, Cell.

[9]  L. Liao,et al.  Role of interleukin-1 receptor type II in the pathogenesis of endometriosis. , 2008, Fertility and sterility.

[10]  E. Thomas,et al.  Microsatellite analysis of endometriosis reveals loss of heterozygosity at candidate ovarian tumor suppressor gene loci. , 1996, Cancer research.

[11]  Lincoln Stein,et al.  Reactome knowledgebase of human biological pathways and processes , 2008, Nucleic Acids Res..

[12]  P. Stenson,et al.  The Human Gene Mutation Database: 2008 update , 2009, Genome Medicine.

[13]  Stephen C. Harris,et al.  atBioNet– an integrated network analysis tool for genomics and biomarker discovery , 2012, BMC Genomics.

[14]  Xiaowei Xu,et al.  SCAN: a structural clustering algorithm for networks , 2007, KDD '07.

[15]  R. Brem,et al.  XRCC1 is required for DNA single-strand break repair in human cells , 2005, Nucleic acids research.

[16]  Ron Shamir,et al.  SPIKE – a database, visualization and analysis tool of cellular signaling pathways , 2008, BMC Bioinformatics.

[17]  J. Lang,et al.  Differentially expressed genes in human endometrial endothelial cells derived from eutopic endometrium of patients with endometriosis compared with those from patients without endometriosis. , 2007, Human reproduction.

[18]  R. Wu,et al.  Growth mechanisms of endometriotic cells in implanted places: a review , 2012, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[19]  S. Missmer,et al.  Endometriosis: a high-risk population for major chronic diseases? , 2015, Human reproduction update.

[20]  F. Tsai,et al.  Interleukin-2 receptor beta (IL-2R beta)-627*C homozygote but not IL-12R beta 1 codon 378 or IL-18 105 polymorphism is associated with higher susceptibility to endometriosis. , 2005, Fertility and sterility.

[21]  Ioannis Xenarios,et al.  DIP: the Database of Interacting Proteins , 2000, Nucleic Acids Res..

[22]  Gillian Murphy,et al.  Structure and function of matrix metalloproteinases and TIMPs. , 2006, Cardiovascular research.

[23]  K. Shuai,et al.  Regulation of JAK–STAT signalling in the immune system , 2003, Nature Reviews Immunology.

[24]  E. Schadt Molecular networks as sensors and drivers of common human diseases , 2009, Nature.

[25]  Richard D. Wood,et al.  Human DNA Repair Genes , 2001, Science.

[26]  C. Tayade,et al.  Pathophysiology and Immune Dysfunction in Endometriosis , 2015, BioMed research international.

[27]  N. Terakawa,et al.  Role of cytokines in endometriosis. , 2001, Fertility and sterility.

[28]  Pardis C Sabeti,et al.  A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC , 2006, Nature Genetics.

[29]  Chih-ping Chen,et al.  XRCC1 399*Arg-related genotype and allele, but not XRCC1 His107Arg, XRCC1 Trp194Arg, KCNQ2, AT1R, and hOGG1 polymorphisms, are associated with higher susceptibility of endometriosis , 2012, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[30]  Livia Perfetto,et al.  MINT, the molecular interaction database: 2012 update , 2011, Nucleic Acids Res..

[31]  K. Gunsalus,et al.  Network modeling links breast cancer susceptibility and centrosome dysfunction. , 2007, Nature genetics.

[32]  Jeng-Jong Hwang,et al.  The role of apurinic/apyrimidinic endonuclease DNA repair gene in endometriosis. , 2014, Cancer genomics & proteomics.

[33]  L. Tamer,et al.  Functional association of interleukin-18 gene -607 C/A promoter polymorphisms with endometriosis. , 2011, Fertility and sterility.

[34]  W. Dmowski,et al.  Endometriosis: abnormal endometrium and dysfunctional immune response. , 1998, Current opinion in obstetrics & gynecology.

[35]  Laura Inés Furlong,et al.  DisGeNET: a Cytoscape plugin to visualize, integrate, search and analyze gene-disease networks , 2010, Bioinform..

[36]  Jennifer M. Rust,et al.  The BioGRID Interaction Database , 2011 .

[37]  X. Zhang,et al.  Alteration of focal adhesion kinase expression in eutopic endometrium of women with endometriosis. , 2008, Fertility and sterility.

[38]  T. Yoshikawa,et al.  Association of HLA class I and class II alleles with susceptibility to endometriosis. , 2002, Human immunology.

[39]  A. Barabasi,et al.  A Protein–Protein Interaction Network for Human Inherited Ataxias and Disorders of Purkinje Cell Degeneration , 2006, Cell.

[40]  W. Nothnick Treating endometriosis as an autoimmune disease. , 2001, Fertility and sterility.

[41]  T. Motoyama,et al.  Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary , 2006, Modern Pathology.

[42]  Alan F. Scott,et al.  Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders , 2002, Nucleic Acids Res..

[43]  P. Schembri-Wismayer,et al.  Molecular links between endometriosis and cancer , 2012, Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology.

[44]  J. Tschopp,et al.  The inflammasome: a danger sensing complex triggering innate immunity. , 2007, Current opinion in immunology.

[45]  Todd F. DeLuca,et al.  Genotator: A disease-agnostic tool for genetic annotation of disease , 2010, BMC Medical Genomics.

[46]  K. Osteen,et al.  Matrix Metalloproteinases and Endometriosis , 2003, Seminars in reproductive medicine.

[47]  P. Courtoy,et al.  Matrix metalloproteinase-27 is expressed in CD163+/CD206+ M2 macrophages in the cycling human endometrium and in superficial endometriotic lesions. , 2014, Molecular human reproduction.

[48]  L. Stein,et al.  A human functional protein interaction network and its application to cancer data analysis , 2010, Genome Biology.

[49]  V. Kähäri,et al.  Matrix metalloproteinases in inflammation. , 2014, Biochimica et biophysica acta.

[50]  Rafael C. Jimenez,et al.  The IntAct molecular interaction database in 2012 , 2011, Nucleic Acids Res..

[51]  E. Baracat,et al.  Endometriosis: an inflammatory disease with a Th2 immune response component. , 2007, Human reproduction.

[52]  S. Kyurkchiev,et al.  Endoglin (cd105) and S100A13 as markers of active angiogenesis in endometriosis. , 2005, Reproductive biology.

[53]  N. Vlahos,et al.  Endometriosis, in vitro fertilisation and the risk of gynaecological malignancies, including ovarian and breast cancer. , 2010, Best practice & research. Clinical obstetrics & gynaecology.

[54]  S. Young,et al.  Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients. , 2016, Fertility and sterility.