Pathway crosstalk analysis in prostate cancer based on protein-protein network data

Prostate cancer (PCa) is one of the major leading cause in men and no effective biomarkers or therapy have been approved for it to date. This study aimed to explore the molecular mechanisms and identify the potential molecular biomarkers of PCa. The microarray profile GSE38241 including 18 prostate cancer metastasis and 21 normal prostate samples was retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by Limma. DEGs functions were investigated by Gene Ontology (GO) and pathway enrichment analysis. Moreover, protein-protein interaction (PPI) network of DEGs was constructed, followed by functional analysis of modules. Additionally, pathway crosstalk network was constructed by integrating PPI network and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Totally, 334 up – and 703 down-regulated DEGs were identified. The functions of up-regulated DEGs were significantly enriched in GO terms of cell cycle phase and cell cycle process. While down-regulated DEGs mainly participated in actin filament-based process. Among these pathways in the pathway crosstalk network, T cell receptor signaling pathway, chemokine signaling pathways, endometrial cancer and glioma were found to play critical roles during PC progression. Cell division cycle 45 (CDC45), baculoviral IAP repeat containing 5 (BIRC5) and cell division cycle associated 5 (CDCA5) may be useful markers for predicting tumor metastasis and therapeutic targets for the treatment of PCa patients. Moreover, the pathway crosstalk network provides the groundwork that targeting multiple pathways might be more effective than targeting one pathway alone.

[1]  J. Droz,et al.  Insulin-Like Growth Factor (IGF) family and prostate cancer. , 2006, Critical reviews in oncology/hematology.

[2]  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 .

[3]  W. Isaacs,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Pathological and Molecular Aspects of Prostate Cancer Prostate Cancer Ii , 2022 .

[4]  Kathleen R. Cho,et al.  Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. , 1997, Cancer research.

[5]  Michael Kohl,et al.  Cytoscape: software for visualization and analysis of biological networks. , 2011, Methods in molecular biology.

[6]  F. Grosse,et al.  Human Cdc45 is a proliferation‐associated antigen , 2007, The FEBS journal.

[7]  Yusuke Nakamura,et al.  Molecular and Cellular Pathobiology Cancer Research Phosphorylation and Activation of Cell Division Cycle Associated 5 by Mitogen-Activated Protein Kinase Play a Crucial Role in Human Lung Carcinogenesis , 2010 .

[8]  Y. Benjamini,et al.  Controlling the false discovery rate in behavior genetics research , 2001, Behavioural Brain Research.

[9]  C. Vaziri,et al.  The Chk1-mediated S-phase Checkpoint Targets Initiation Factor Cdc45 via a Cdc25A/Cdk2-independent Mechanism* , 2006, Journal of Biological Chemistry.

[10]  Wancai Yang,et al.  Soy isoflavones and prostate cancer: A review of molecular mechanisms , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[11]  A. Berchuck,et al.  PTEN/MMAC1 mutations in endometrial cancers. , 1997, Cancer research.

[12]  Hai Zhang,et al.  GenCLiP 2.0: a web server for functional clustering of genes and construction of molecular networks based on free terms , 2014, Bioinform..

[13]  S. Hembruff,et al.  Chemokine signaling in cancer: Implications on the tumor microenvironment and therapeutic targeting. , 2009, Cancer therapy.

[14]  Zhi-Ping Liu,et al.  Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains , 2010, BMC Systems Biology.

[15]  Martin J. Aryee,et al.  DNA Methylation Alterations Exhibit Intraindividual Stability and Interindividual Heterogeneity in Prostate Cancer Metastases , 2013, Science Translational Medicine.

[16]  C. Moreno.  The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways. , 2010, The American journal of pathology.

[17]  L. Pardo,et al.  Potassium channels in cell cycle and cell proliferation , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[18]  Y. Asmann,et al.  A Tissue Biomarker Panel Predicting Systemic Progression after PSA Recurrence Post-Definitive Prostate Cancer Therapy , 2008, PloS one.

[19]  E. Ozkan.  Plasma and tissue insulin-like growth factor-I receptor (IGF-IR) as a prognostic marker for prostate cancer and anti-IGF-IR agents as novel therapeutic strategy for refractory cases: A review , 2011, Molecular and Cellular Endocrinology.

[20]  Lynette M. Smith,et al.  Aberrant expression of E-cadherin and beta-catenin in human prostate cancer. , 2005, Urologic oncology.

[21]  G. Mills,et al.  MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. , 1997, Cancer research.

[22]  Karl Mechtler,et al.  Sororin Is Required for Stable Binding of Cohesin to Chromatin and for Sister Chromatid Cohesion in Interphase , 2007, Current Biology.

[23]  J. Diffley,et al.  DNA synthesis at individual replication forks requires the essential initiation factor Cdc45p , 2000, The EMBO journal.

[24]  Mirko Francesconi,et al.  Reconstructing networks of pathways via significance analysis of their intersections , 2008, BMC Bioinformatics.

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

[26]  Pankaj Agarwal,et al.  A global pathway crosstalk network , 2008, Bioinform..

[27]  J. Hoeijmakers.  Genome maintenance mechanisms for preventing cancer , 2001, Nature.

[28]  Haiyuan Yu,et al.  Detecting overlapping protein complexes in protein-protein interaction networks , 2012, Nature Methods.

[29]  C. D. Savci-Heijink,et al.  Identification of Prognostic Biomarkers for Prostate Cancer , 2008, Clinical Cancer Research.

[30]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[31]  R. Hubert,et al.  STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[33]  Shengkun Sun,et al.  Genomic profiling screens small molecules of metastatic prostate carcinoma. , 2015, Oncology letters.

[34]  R. McLendon,et al.  PTEN gene mutations are seen in high-grade but not in low-grade gliomas. , 1997, Cancer research.

[35]  F. Hamdy,et al.  [Early diagnosis and surgical management of prostate cancer]. , 2003, Annales d'urologie.

[36]  Jihyeung Ju,et al.  Inhibition of IGF-1 Signaling by Genistein: Modulation of E-Cadherin Expression and Downregulation of β-Catenin Signaling in Hormone Refractory PC-3 Prostate Cancer Cells , 2012, Nutrition and cancer.

[37]  Arturo Molina,et al.  Abiraterone and increased survival in metastatic prostate cancer. , 2011, The New England journal of medicine.

[38]  M. Cooperberg,et al.  Comparative risk‐adjusted mortality outcomes after primary surgery, radiotherapy, or androgen‐deprivation therapy for localized prostate cancer , 2010, Cancer.

[39]  M. Peshwa,et al.  Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  G. Lazennec,et al.  Emerging roles of chemokines in prostate cancer. , 2009, Endocrine-related cancer.

[41]  H. Takisawa,et al.  Central role for Cdc45 in establishing an initiation complex of DNA replication in Xenopus egg extracts , 2000, Genes to cells : devoted to molecular & cellular mechanisms.

[42]  Gordon K Smyth,et al.  Statistical Applications in Genetics and Molecular Biology Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2011 .

[43]  Steven Piantadosi,et al.  Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. , 2003, The Journal of urology.

[44]  Damian Szklarczyk,et al.  STRING v9.1: protein-protein interaction networks, with increased coverage and integration , 2012, Nucleic Acids Res..

[45]  Jian Li,et al.  Identifying differentially expressed genes and small molecule drugs for prostate cancer by a bioinformatics strategy. , 2013, Asian Pacific journal of cancer prevention : APJCP.