{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T18:40:34Z","timestamp":1748198434723},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2018,7,23]],"date-time":"2018-07-23T00:00:00Z","timestamp":1532304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Research Grants Council of Hong Kong","award":["HKU 17127014"],"award-info":[{"award-number":["HKU 17127014"]}]},{"name":"General Research Fund","award":["HKU T12-710\/16R"],"award-info":[{"award-number":["HKU T12-710\/16R"]}]},{"name":"Theme-based Research Scheme"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>During cancer stage transition, a master regulator (MR) refers to the key gene controlling cancer initiation and progression by orchestrating the associated target genes (termed as its regulon). Due to their inherent importance, MRs can serve as critical biomarkers for cancer diagnosis and prognosis, and therapeutic targets. However, it is challenging to infer key MRs that might explain gene expression profile changes between two groups due to lack of context-specific regulons, whose expression level can collectively reflect the activity of likely MRs. There is also a need to design an easy-to-use tool of MR identification for research community.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>First, we generated cancer-specific regulons for 26 cancer types by analyzing high-throughput omics data from TCGA, and extracted noncancer-specific regulons from public databases. We subsequently developed a web server MR4Cancer, integrating the regulons with statistical inference to identify and prioritize MRs driving a phenotypic divergence of interest. Based on the input gene list (e.g. differentially expressed genes) or expression profile with two groups, MR4Cancer outputs ranked MRs by enrichment testing against the predefined regulons. Gene Ontology and canonical pathway analyses are also conducted to elucidate the function of likely MRs. Moreover, MR4Cancer provides dynamic network visualization for MR-target relations, and users can interactively interrogate the network to produce new hypotheses and high-quality figures for publication. Finally, the presented case studies highlighted the performance of MR4Cancer. We expect this user-friendly and powerful web tool will provide researchers novel insights into tumorigenesis and therapeutic intervention.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>http:\/\/cis.hku.hk\/MR4Cancer<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty658","type":"journal-article","created":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T13:59:58Z","timestamp":1532095198000},"page":"636-642","source":"Crossref","is-referenced-by-count":9,"title":["MR4Cancer: a web server prioritizing master regulators for cancer"],"prefix":"10.1093","volume":"35","author":[{"given":"Beibei","family":"Ru","sequence":"first","affiliation":[{"name":"School of Biological Sciences, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yin","family":"Tong","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,7,23]]},"reference":[{"key":"2023051511005985700_bty658-B1","doi-asserted-by":"crossref","DOI":"10.1093\/database\/baw105","article-title":"FANTOM5 transcriptome catalog of cellular states based on Semantic MediaWiki","volume":"2016","author":"Abugessaisa","year":"2016","journal-title":"Database"},{"key":"2023051511005985700_bty658-B2","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/ng.3593","article-title":"Functional characterization of somatic mutations in cancer using network-based inference of protein activity","volume":"48","author":"Alvarez","year":"2016","journal-title":"Nat. Genet."},{"key":"2023051511005985700_bty658-B3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"2023051511005985700_bty658-B4","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.ccr.2014.03.017","article-title":"Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy","volume":"25","author":"Aytes","year":"2014","journal-title":"Cancer Cell"},{"key":"2023051511005985700_bty658-B5","doi-asserted-by":"crossref","first-page":"D991","DOI":"10.1093\/nar\/gks1193","article-title":"NCBI GEO: archive for functional genomics datasets\u2014update","volume":"41","author":"Barrett","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B6","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.trecan.2015.07.001","article-title":"Targeting transcription factors in cancer","volume":"1","author":"Bhagwat","year":"2015","journal-title":"Trends Cancer"},{"key":"2023051511005985700_bty658-B7","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nrc.2016.124","article-title":"The recurrent architecture of tumour initiation, progression and drug sensitivity","volume":"17","author":"Califano","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"2023051511005985700_bty658-B8","doi-asserted-by":"crossref","first-page":"8878","DOI":"10.1038\/ncomms9878","article-title":"MicroRNA-mRNA interactions underlying colorectal cancer molecular subtypes","volume":"6","author":"Cantini","year":"2015","journal-title":"Nat. Commun."},{"key":"2023051511005985700_bty658-B9","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/nature08712","article-title":"The transcriptional network for mesenchymal transformation of brain tumours","volume":"463","author":"Carro","year":"2010","journal-title":"Nature"},{"key":"2023051511005985700_bty658-B10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/ng.3458","article-title":"Regulators of genetic risk of breast cancer identified by integrative network analysis","volume":"48","author":"Castro","year":"2016","journal-title":"Nat. Genet."},{"key":"2023051511005985700_bty658-B11","doi-asserted-by":"crossref","first-page":"D685","DOI":"10.1093\/nar\/gkq1039","article-title":"Pathway commons, a web resource for biological pathway data","volume":"39","author":"Cerami","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B12","first-page":"e114","article-title":"What is a master regulator? J","volume":"3","author":"Chan","year":"2013","journal-title":"Stem Cell Res. Ther."},{"key":"2023051511005985700_bty658-B13","doi-asserted-by":"crossref","first-page":"D531","DOI":"10.1093\/nar\/gku1009","article-title":"The human DEPhOsphorylation database DEPOD: a 2015 update","volume":"43","author":"Duan","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B14","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1126\/science.aad9512","article-title":"Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation","volume":"352","author":"Dutta","year":"2016","journal-title":"Science"},{"key":"2023051511005985700_bty658-B15","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/nrc3299","article-title":"From cancer genomes to oncogenic drivers, tumour dependencies and therapeutic targets","volume":"12","author":"Eifert","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"2023051511005985700_bty658-B16","doi-asserted-by":"crossref","first-page":"D481","DOI":"10.1093\/nar\/gkv1351","article-title":"The reactome pathway knowledgebase","volume":"44","author":"Fabregat","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B17","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1038\/ncomms3464","article-title":"Master regulators of FGFR2 signalling and breast cancer risk","volume":"4","author":"Fletcher","year":"2013","journal-title":"Nat. Commun."},{"key":"2023051511005985700_bty658-B18","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1158\/0008-5472.CAN-17-1679","article-title":"Transcription factor activities enhance markers of drug sensitivity in cancer","volume":"78","author":"Garcia-Alonso","year":"2018","journal-title":"Cancer Res."},{"key":"2023051511005985700_bty658-B19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev-pharmtox-010510-100517","article-title":"microRNAs: master regulators as potential therapeutics in cancer","volume":"51","author":"Garofalo","year":"2011","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2023051511005985700_bty658-B20","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1093\/bioinformatics\/btr064","article-title":"FIMO: scanning for occurrences of a given motif","volume":"27","author":"Grant","year":"2011","journal-title":"Bioinformatics"},{"key":"2023051511005985700_bty658-B21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"Hanzelmann","year":"2013","journal-title":"BMC Bioinformatics"},{"key":"2023051511005985700_bty658-B22","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3892\/ijo.2013.1951","article-title":"Estrogen receptor 1 gene as a tumor suppressor gene in hepatocellular carcinoma detected by triple-combination array analysis","volume":"43","author":"Hishida","year":"2013","journal-title":"Int. J. Oncol."},{"key":"2023051511005985700_bty658-B23","doi-asserted-by":"crossref","first-page":"D512","DOI":"10.1093\/nar\/gku1267","article-title":"PhosphoSitePlus, 2014: mutations, PTMs and recalibrations","volume":"43","author":"Hornbeck","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B24","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B25","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: a comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B26","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1093\/bioinformatics\/btw216","article-title":"ARACNe-AP: gene network reverse engineering through adaptive partitioning inference of mutual information","volume":"32","author":"Lachmann","year":"2016","journal-title":"Bioinformatics"},{"key":"2023051511005985700_bty658-B27","doi-asserted-by":"crossref","first-page":"R29","DOI":"10.1186\/gb-2014-15-2-r29","article-title":"voom: precision weights unlock linear model analysis tools for RNA-seq read counts","volume":"15","author":"Law","year":"2014","journal-title":"Genome Biol."},{"key":"2023051511005985700_bty658-B28","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature12213","article-title":"Mutational heterogeneity in cancer and the search for new cancer-associated genes","volume":"499","author":"Lawrence","year":"2013","journal-title":"Nature"},{"key":"2023051511005985700_bty658-B29","first-page":"408","article-title":"Computational methods for discovering gene networks from expression data","volume":"10","author":"Lee","year":"2009","journal-title":"Brief. Bioinform."},{"key":"2023051511005985700_bty658-B30","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/msb.2010.31","article-title":"A human B-cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers","volume":"6","author":"Lefebvre","year":"2010","journal-title":"Mol. Syst. Biol."},{"key":"2023051511005985700_bty658-B31","doi-asserted-by":"crossref","first-page":"10271","DOI":"10.18632\/oncotarget.2082","article-title":"High KIF18A expression correlates with unfavorable prognosis in primary hepatocellular carcinoma","volume":"5","author":"Liao","year":"2014","journal-title":"Oncotarget"},{"key":"2023051511005985700_bty658-B32","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The molecular signatures database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"2023051511005985700_bty658-B33","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: an R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"2023051511005985700_bty658-B34","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1158\/0008-5472.CAN-16-1813","article-title":"Master transcriptional regulators in cancer: discovery via reverse engineering approaches and subsequent validation","volume":"77","author":"Moran","year":"2017","journal-title":"Cancer Res."},{"key":"2023051511005985700_bty658-B35","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1089\/152791601750294344","article-title":"Biocarta","volume":"2","author":"Nishimura","year":"2001","journal-title":"Biotechnol. Softw. Internet Rep."},{"key":"2023051511005985700_bty658-B36","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nrd.2016.256","article-title":"Marked for death: targeting epigenetic changes in cancer","volume":"16","author":"Pfister","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"2023051511005985700_bty658-B37","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ccr.2006.02.019","article-title":"Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis","volume":"9","author":"Phillips","year":"2006","journal-title":"Cancer Cell"},{"key":"2023051511005985700_bty658-B38","doi-asserted-by":"crossref","first-page":"W83","DOI":"10.1093\/nar\/gkw199","article-title":"g:Profiler\u2014a web server for functional interpretation of gene lists (2016 update)","volume":"44","author":"Reimand","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B39","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B40","doi-asserted-by":"crossref","first-page":"D918","DOI":"10.1093\/nar\/gkx877","article-title":"CR2Cancer: a database for chromatin regulators in human cancer","volume":"46","author":"Ru","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B41","doi-asserted-by":"crossref","first-page":"D674","DOI":"10.1093\/nar\/gkn653","article-title":"PID: the pathway interaction database","volume":"37","author":"Schaefer","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B42","doi-asserted-by":"crossref","first-page":"e1002223","DOI":"10.1371\/journal.pmed.1002223","article-title":"Master Regulators of Oncogenic KRAS Response in Pancreatic Cancer: an Integrative Network Biology Analysis","volume":"14","author":"Sivakumar","year":"2017","journal-title":"PLoS Med."},{"key":"2023051511005985700_bty658-B43","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023051511005985700_bty658-B44","doi-asserted-by":"crossref","first-page":"3085","DOI":"10.1038\/onc.2014.254","article-title":"MicroRNA regulons in tumor microenvironment","volume":"34","author":"Suzuki","year":"2015","journal-title":"Oncogene"},{"key":"2023051511005985700_bty658-B45","doi-asserted-by":"crossref","first-page":"10778","DOI":"10.18632\/oncotarget.2502","article-title":"Paradoxical role of CBX8 in proliferation and metastasis of colorectal cancer","volume":"5","author":"Tang","year":"2014","journal-title":"Oncotarget"},{"key":"2023051511005985700_bty658-B46","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13059-018-1442-0","article-title":"MICMIC: identification of DNA methylation of distal regulatory regions with causal effects on tumorigenesis","volume":"19","author":"Tong","year":"2018","journal-title":"Genome Biol."},{"key":"2023051511005985700_bty658-B47","doi-asserted-by":"crossref","first-page":"W130","DOI":"10.1093\/nar\/gkx356","article-title":"WebGestalt 2017: a more comprehensive, powerful, flexible and interactive gene set enrichment analysis toolkit","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2023051511005985700_bty658-B48","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1038\/nprot.2013.150","article-title":"Target analysis by integration of transcriptome and ChIP-seq data with BETA","volume":"8","author":"Wang","year":"2013","journal-title":"Nat. Protoc."},{"key":"2023051511005985700_bty658-B49","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The cancer genome atlas pan-cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/4\/636\/50321174\/bioinformatics_35_4_636.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/4\/636\/50321174\/bioinformatics_35_4_636.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T11:02:29Z","timestamp":1684148549000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/4\/636\/5057159"}},"subtitle":[],"editor":[{"given":"John","family":"Hancock","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2018,7,23]]},"references-count":49,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,2,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/bty658","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,2,15]]},"published":{"date-parts":[[2018,7,23]]}}}