title: Integrated network model provides new insights into castration-resistant prostate cancer.
abstract: Castration-resistant prostate cancer (CRPC) is the main challenge for prostate cancer treatment. Recent studies have indicated that extending the treatments to simultaneously targeting different pathways could provide better approaches. To better understand the regulatory functions of different pathways, a system-wide study of CRPC regulation is necessary. For this purpose, we constructed a comprehensive CRPC regulatory network by integrating multiple pathways such as the MEK/ERK and the PI3K/AKT pathways. We studied the feedback loops of this network and found that AKT was involved in all detected negative feedback loops. We translated the network into a predictive Boolean model and analyzed the stable states and the control effects of genes using novel methods. We found that the stable states naturally divide into two obvious groups characterizing PC3 and DU145 cells respectively. Stable state analysis further revealed that several critical genes, such as PTEN, AKT, RAF, and CDKN2A, had distinct expression behaviors in different clusters. Our model predicted the control effects of many genes. We used several public datasets as well as FHL2 overexpression to verify our finding. The results of this study can help in identifying potential therapeutic targets, especially simultaneous targets of multiple pathways, for CRPC.
authors.affiliation: Experimental Centre of Medical Sciences, Guangxi Medical University, Nanning, Guangxi, 530021, China.|Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, 530021, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Experimental Centre of Medical Sciences, Guangxi Medical University, Nanning, Guangxi, 530021, China.
authors.forename: Yinmin
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Experimental Centre of Medical Sciences, Guangxi Medical University, Nanning, Guangxi, 530021, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Experimental Centre of Medical Sciences, Guangxi Medical University, Nanning, Guangxi, 530021, China.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA.
authors.forename: Yi Ming
authors.initials: YM
authors.lastname: Zou
mesh_terms: D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D016208:Databases, Factual; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C105987:FHL2 protein, human; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human