{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:16:30Z","timestamp":1767179790276,"version":"build-2238731810"},"reference-count":128,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2015,6,17]],"date-time":"2015-06-17T00:00:00Z","timestamp":1434499200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1004202","type":"journal-article","created":{"date-parts":[[2015,6,17]],"date-time":"2015-06-17T14:31:09Z","timestamp":1434551469000},"page":"e1004202","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Deciphering Signaling Pathway Networks to Understand the Molecular Mechanisms of Metformin Action"],"prefix":"10.1371","volume":"11","author":[{"given":"Jingchun","family":"Sun","sequence":"first","affiliation":[]},{"given":"Min","family":"Zhao","sequence":"additional","affiliation":[]},{"given":"Peilin","family":"Jia","sequence":"additional","affiliation":[]},{"given":"Lily","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Yonghui","family":"Wu","sequence":"additional","affiliation":[]},{"given":"Carissa","family":"Iverson","sequence":"additional","affiliation":[]},{"given":"Yubo","family":"Zhou","sequence":"additional","affiliation":[]},{"given":"Erica","family":"Bowton","sequence":"additional","affiliation":[]},{"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[]},{"given":"Joshua C.","family":"Denny","sequence":"additional","affiliation":[]},{"given":"Melinda C.","family":"Aldrich","sequence":"additional","affiliation":[]},{"given":"Hua","family":"Xu","sequence":"additional","affiliation":[]},{"given":"Zhongming","family":"Zhao","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2015,6,17]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nrd892","article-title":"The druggable genome","volume":"1","author":"AL Hopkins","year":"2002","journal-title":"Nat Rev Drug Discov"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrd3478","article-title":"Trends in the exploitation of novel drug targets","volume":"10","author":"M Rask-Andersen","year":"2011","journal-title":"Nat Rev Drug Discov"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"re1","DOI":"10.1126\/scisignal.2002961","article-title":"Computational approaches for analyzing information flow in biological networks","volume":"5","author":"B Kholodenko","year":"2012","journal-title":"Sci Signal"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1038\/3553","article-title":"Signal transduction as a drug-discovery platform","volume":"16","author":"A Persidis","year":"1998","journal-title":"Nat Biotechnol"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrg2538","article-title":"A census of human transcription factors: function, expression and evolution","volume":"10","author":"JM Vaquerizas","year":"2009","journal-title":"Nat Rev Genet"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nature04869","article-title":"Ras, PI(3)K and mTOR signalling controls tumour cell growth","volume":"441","author":"RJ Shaw","year":"2006","journal-title":"Nature"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nature04871","article-title":"Hypoxia signalling in cancer and approaches to enforce tumour regression","volume":"441","author":"J Pouyssegur","year":"2006","journal-title":"Nature"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.tips.2010.05.004","article-title":"Signaling pathways in schizophrenia: emerging targets and therapeutic strategies","volume":"31","author":"CS Karam","year":"2010","journal-title":"Trends Pharmacol Sci"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1210\/me.2008-0135","article-title":"The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus","volume":"22","author":"T Jin","year":"2008","journal-title":"Mol Endocrinol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.ejca.2005.07.034","article-title":"Key cancer cell signal transduction pathways as therapeutic targets","volume":"42","author":"R Bianco","year":"2006","journal-title":"Eur J Cancer"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1176\/appi.ajp.2009.08121873","article-title":"Roles of the Akt\/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action","volume":"167","author":"Z Freyberg","year":"2010","journal-title":"Am J Psychiatry"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/nrd3810","article-title":"Targeting the TGFbeta signalling pathway in disease","volume":"11","author":"RJ Akhurst","year":"2012","journal-title":"Nat Rev Drug Discov"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature04874","article-title":"Mechanisms of drug inhibition of signalling molecules","volume":"441","author":"JS Sebolt-Leopold","year":"2006","journal-title":"Nature"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1158\/0008-5472.CAN-11-2333","article-title":"A novel method of transcriptional response analysis to facilitate drug repositioning for cancer therapy","volume":"72","author":"G Jin","year":"2012","journal-title":"Cancer Res"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease","volume":"313","author":"J Lamb","year":"2006","journal-title":"Science"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"D1035","DOI":"10.1093\/nar\/gkq1126","article-title":"DrugBank 3.0: a comprehensive resource for 'omics' research on drugs","volume":"39","author":"C Knox","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"D109","DOI":"10.1093\/nar\/gkr988","article-title":"KEGG for integration and interpretation of large-scale molecular data sets","volume":"40","author":"M Kanehisa","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1080\/03602530802413338","article-title":"PharmGKB: understanding the effects of individual genetic variants","volume":"40","author":"K Sangkuhl","year":"2008","journal-title":"Drug Metab Rev"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"D401","DOI":"10.1093\/nar\/gkt1207","article-title":"STITCH 4: integration of protein-chemical interactions with user data","volume":"42","author":"M Kuhn","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/clpt.2010.91","article-title":"Network systems biology for drug discovery","volume":"88","author":"DK Arrell","year":"2010","journal-title":"Clin Pharmacol Ther"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: the next paradigm in drug discovery","volume":"4","author":"AL Hopkins","year":"2008","journal-title":"Nat Chem Biol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.cell.2011.02.016","article-title":"Interactome networks and human disease","volume":"144","author":"M Vidal","year":"2011","journal-title":"Cell"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1093\/bib\/bbs043","article-title":"Network-based drug discovery by integrating systems biology and computational technologies","volume":"14","author":"EL Leung","year":"2013","journal-title":"Brief Bioinform"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1158\/1535-7163.MCT-09-1186","article-title":"Metformin in cancer therapy: a new perspective for an old antidiabetic drug?","volume":"9","author":"I Ben Sahra","year":"2010","journal-title":"Mol Cancer Ther"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/onc.2012.181","article-title":"Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects","volume":"32","author":"MA Pierotti","year":"2013","journal-title":"Oncogene"},{"key":"ref26","article-title":"J Am Med Inform Assoc","author":"H Xu","year":"2014"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: a network-based approach to human disease","volume":"12","author":"AL Barabasi","year":"2011","journal-title":"Nat Rev Genet"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1093\/bioinformatics\/btq076","article-title":"The power of protein interaction networks for associating genes with diseases","volume":"26","author":"S Navlakha","year":"2010","journal-title":"Bioinformatics"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"9362","DOI":"10.1073\/pnas.0903103106","article-title":"Potential etiologic and functional implications of genome-wide association loci for human diseases and traits","volume":"106","author":"LA Hindorff","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nrc1299","article-title":"A census of human cancer genes","volume":"4","author":"PA Futreal","year":"2004","journal-title":"Nat Rev Cancer"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature05911","article-title":"Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls","volume":"447","year":"2007","journal-title":"Nature"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/ng2075","article-title":"A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer","volume":"39","author":"DJ Hunter","year":"2007","journal-title":"Nat Genet"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1038\/ng.429","article-title":"Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer","volume":"41","author":"L Amundadottir","year":"2009","journal-title":"Nat Genet"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"234cm233","DOI":"10.1126\/scitranslmed.3008604","article-title":"Biobanks and electronic medical records: enabling cost-effective research","volume":"6","author":"E Bowton","year":"2014","journal-title":"Sci Transl Med"},{"key":"ref35","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":"EG Cerami","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"D108","DOI":"10.1093\/nar\/gkj143","article-title":"TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes","volume":"34","author":"V Matys","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"ref37","first-page":"422","article-title":"Ranking gene-drug relationships in biomedical literature using Latent Dirichlet Allocation","author":"Y Wu","year":"2012","journal-title":"Pac Symp Biocomput"},{"key":"ref38","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":"A Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/ng1578","article-title":"Mining for regulatory programs in the cancer transcriptome","volume":"37","author":"DR Rhodes","year":"2005","journal-title":"Nat Genet"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"R77","DOI":"10.1186\/gb-2007-8-5-r77","article-title":"Revealing signaling pathway deregulation by using gene expression signatures and regulatory motif analysis","volume":"8","author":"Y Liu","year":"2007","journal-title":"Genome Biol"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrg1272","article-title":"Network biology: understanding the cell's functional organization","volume":"5","author":"AL Barabasi","year":"2004","journal-title":"Nat Rev Genet"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"e1000140","DOI":"10.1371\/journal.pcbi.1000140","article-title":"Why do hubs in the yeast protein interaction network tend to be essential: reexamining the connection between the network topology and essentiality","volume":"4","author":"E Zotenko","year":"2008","journal-title":"PLoS Comput Biol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"e5815","DOI":"10.1371\/journal.pone.0005815","article-title":"Influence of protein abundance on high-throughput protein-protein interaction detection","volume":"4","author":"J Ivanic","year":"2009","journal-title":"PLoS One"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"4205","DOI":"10.1093\/bioinformatics\/bti688","article-title":"Interactome-transcriptome analysis reveals the high centrality of genes differentially expressed in lung cancer tissues","volume":"21","author":"S Wachi","year":"2005","journal-title":"Bioinformatics"},{"issue":"Suppl 3","key":"ref45","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1186\/1471-2164-11-S3-S5","article-title":"A comparative study of cancer proteins in the human protein-protein interaction network","volume":"11","author":"J Sun","year":"2010","journal-title":"BMC Genomics"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.tig.2004.04.008","article-title":"Genomic analysis of essentiality within protein networks","volume":"20","author":"H Yu","year":"2004","journal-title":"Trends Genet"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1038\/sj.onc.1210421","article-title":"MAP kinase signalling pathways in cancer","volume":"26","author":"AS Dhillon","year":"2007","journal-title":"Oncogene"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/embor.2010.160","article-title":"MAPK signalling in cellular metabolism: stress or wellness?","volume":"11","author":"H Gehart","year":"2010","journal-title":"EMBO Rep"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"W77","DOI":"10.1093\/nar\/gkt439","article-title":"WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013","volume":"41","author":"J Wang","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/cas.12043","article-title":"Diabetes mellitus and cancer risk: review of the epidemiological evidence","volume":"104","author":"K Shikata","year":"2013","journal-title":"Cancer Sci"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1038\/sj.onc.1202746","article-title":"MYC oncogenes and human neoplastic disease","volume":"18","author":"CE Nesbit","year":"1999","journal-title":"Oncogene"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"7776","DOI":"10.1073\/pnas.1111135109","article-title":"Transcription factors c-Myc and CDX2 mediate E-selectin ligand expression in colon cancer cells undergoing EGF\/bFGF-induced epithelial-mesenchymal transition","volume":"109","author":"K Sakuma","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1128\/MCB.24.10.4294-4308.2004","article-title":"Visualization of Myc\/Max\/Mad family dimers and the competition for dimerization in living cells","volume":"24","author":"AV Grinberg","year":"2004","journal-title":"Mol Cell Biol"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1186\/1471-2164-10-314","article-title":"In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach","volume":"10","author":"L Chavez","year":"2009","journal-title":"BMC Genomics"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1093\/nar\/28.3.669","article-title":"Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT)","volume":"28","author":"S Kyo","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"7173","DOI":"10.1158\/1078-0432.CCR-08-0850","article-title":"Human telomerase reverse transcriptase activated by E6 oncoprotein is required for human papillomavirus-16\/18-infected lung tumorigenesis","volume":"14","author":"YW Cheng","year":"2008","journal-title":"Clin Cancer Res"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1093\/nar\/gkl1157","article-title":"Identifying synergistic regulation involving c-Myc and sp1 in human tissues","volume":"35","author":"F Parisi","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"4510","DOI":"10.1073\/pnas.081074898","article-title":"Myc represses the p21(WAF1\/CIP1) promoter and interacts with Sp1\/Sp3","volume":"98","author":"AL Gartel","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.molmet.2013.09.002","article-title":"Genetic and epigenetic control of metabolic health","volume":"2","author":"RW Schwenk","year":"2013","journal-title":"Mol Metab"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"322","DOI":"10.2337\/dc09-1380","article-title":"Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16","volume":"33","author":"GW Landman","year":"2010","journal-title":"Diabetes Care"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1093\/carcin\/bgt231","article-title":"Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors","volume":"34","author":"V Nair","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/j.1752-8062.2010.00175.x","article-title":"Principles of human subjects protections applied in an opt-out, de-identified biobank","volume":"3","author":"J Pulley","year":"2010","journal-title":"Clin Transl Sci"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1093\/bioinformatics\/btl039","article-title":"CFinder: locating cliques and overlapping modules in biological networks","volume":"22","author":"B Adamcsek","year":"2006","journal-title":"Bioinformatics"},{"issue":"Suppl 2","key":"ref64","doi-asserted-by":"crossref","first-page":"S362","DOI":"10.2337\/dc09-S340","article-title":"Adipocytokines and insulin resistance: the possible role of lipocalin-2, retinol binding protein-4, and adiponectin","volume":"32","author":"E Esteve","year":"2009","journal-title":"Diabetes Care"},{"issue":"Suppl 9","key":"ref65","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1093\/ajhp\/59.suppl_9.S3","article-title":"Insulin resistance, diabetes, and the adipocyte","volume":"59","author":"MW Stolar","year":"2002","journal-title":"Am J Health Syst Pharm"},{"key":"ref66","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1126\/science.1092952","article-title":"Insulin signaling in health and disease","volume":"302","author":"MF White","year":"2003","journal-title":"Science"},{"key":"ref67","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1749-8104-5-7","article-title":"Insulin receptor signaling in the development of neuronal structure and function","volume":"5","author":"SL Chiu","year":"2010","journal-title":"Neural Dev"},{"issue":"Pt 3","key":"ref68","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1042\/bj3480607","article-title":"Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain","volume":"348","author":"MR Owen","year":"2000","journal-title":"Biochem J"},{"key":"ref69","doi-asserted-by":"crossref","first-page":"e02242","DOI":"10.7554\/eLife.02242","article-title":"Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis","volume":"3","author":"WW Wheaton","year":"2014","journal-title":"Elife"},{"key":"ref70","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nrm3311","article-title":"AMPK: a nutrient and energy sensor that maintains energy homeostasis","volume":"13","author":"DG Hardie","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref71","article-title":"AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease","author":"DG Hardie","year":"2014","journal-title":"J Intern Med"},{"key":"ref72","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrc2676","article-title":"The LKB1-AMPK pathway: metabolism and growth control in tumour suppression","volume":"9","author":"DB Shackelford","year":"2009","journal-title":"Nat Rev Cancer"},{"key":"ref73","first-page":"1642","article-title":"Science","volume":"310","author":"RJ Shaw","year":"2005"},{"key":"ref74","first-page":"925","article-title":"Oncol Rep","volume":"21","author":"X Liang","year":"2009"},{"key":"ref75","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/ncomms1859","article-title":"Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC","volume":"3","author":"G Blandino","year":"2012","journal-title":"Nat Commun"},{"key":"ref76","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1093\/carcin\/bgt307","article-title":"Metformin targets c-MYC oncogene to prevent prostate cancer","volume":"34","author":"T Akinyeke","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref77","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1093\/carcin\/bgp268","article-title":"Telomeres and telomerase in cancer","volume":"31","author":"SE Artandi","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref78","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/6010","article-title":"Direct activation of TERT transcription by c-MYC","volume":"21","author":"KJ Wu","year":"1999","journal-title":"Nat Genet"},{"key":"ref79","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.2337\/diabetes.51.6.1793","article-title":"Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes","volume":"51","author":"DR Laybutt","year":"2002","journal-title":"Diabetes"},{"key":"ref80","doi-asserted-by":"crossref","first-page":"12998","DOI":"10.1074\/jbc.M111148200","article-title":"Induction of c-Myc expression suppresses insulin gene transcription by inhibiting NeuroD\/BETA2-mediated transcriptional activation","volume":"277","author":"H Kaneto","year":"2002","journal-title":"J Biol Chem"},{"key":"ref81","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1677\/jme.0.0290265","article-title":"Role of Sp1 in insulin regulation of gene expression","volume":"29","author":"SL Samson","year":"2002","journal-title":"J Mol Endocrinol"},{"key":"ref82","first-page":"1147","article-title":"Regulation of insulin-like growth factor I receptor gene expression by Sp1: physical and functional interactions of Sp1 at GC boxes and at a CT element","volume":"9","author":"D Beitner-Johnson","year":"1995","journal-title":"Mol Endocrinol"},{"key":"ref83","doi-asserted-by":"crossref","first-page":"37","DOI":"10.4161\/isl.2.1.10196","article-title":"c-Myc directly induces both impaired insulin secretion and loss of beta-cell mass, independently of hyperglycemia in vivo","volume":"2","author":"L Cheung","year":"2010","journal-title":"Islets"},{"key":"ref84","doi-asserted-by":"crossref","first-page":"e32590","DOI":"10.1371\/journal.pone.0032590","article-title":"Gene expression of the tumour suppressor LKB1 is mediated by Sp1, NF-Y and FOXO transcription factors","volume":"7","author":"N Lutzner","year":"2012","journal-title":"PLoS One"},{"key":"ref85","doi-asserted-by":"crossref","first-page":"3851","DOI":"10.1038\/onc.2013.353","article-title":"LKB1 loss by alteration of the NKX2-1\/p53 pathway promotes tumor malignancy and predicts poor survival and relapse in lung adenocarcinomas","volume":"33","author":"LH Tsai","year":"2014","journal-title":"Oncogene"},{"key":"ref86","doi-asserted-by":"crossref","first-page":"E1839","DOI":"10.1073\/pnas.1208530110","article-title":"Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosis","volume":"110","author":"AI Nieminen","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref87","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1530\/JOE-12-0054","article-title":"Adiponectin inhibits KISS1 gene transcription through AMPK and specificity protein-1 in the hypothalamic GT1-7 neurons","volume":"214","author":"JP Wen","year":"2012","journal-title":"J Endocrinol"},{"key":"ref88","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.3892\/or.2013.2718","article-title":"Metformin suppresses hepatocellular carcinoma cell growth through induction of cell cycle G1\/G0 phase arrest and p21CIP and p27KIP expression and downregulation of cyclin D1 in vitro and in vivo","volume":"30","author":"X Cai","year":"2013","journal-title":"Oncol Rep"},{"key":"ref89","doi-asserted-by":"crossref","first-page":"24603","DOI":"10.3390\/ijms141224603","article-title":"The antidiabetic drug metformin inhibits the proliferation of bladder cancer cells in vitro and in vivo","volume":"14","author":"T Zhang","year":"2013","journal-title":"Int J Mol Sci"},{"key":"ref90","doi-asserted-by":"crossref","first-page":"3980","DOI":"10.1158\/0008-5472.CAN-04-3995","article-title":"Lost in transcription: p21 repression, mechanisms, and consequences","volume":"65","author":"AL Gartel","year":"2005","journal-title":"Cancer Res"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"e1000655","DOI":"10.1371\/journal.pcbi.1000655","article-title":"How to understand the cell by breaking it: network analysis of gene perturbation screens","volume":"6","author":"F Markowetz","year":"2010","journal-title":"PLoS Comput Biol"},{"key":"ref92","doi-asserted-by":"crossref","first-page":"e1000828","DOI":"10.1371\/journal.pcbi.1000828","article-title":"Plato's cave algorithm: inferring functional signaling networks from early gene expression shadows","volume":"6","author":"Y Shimoni","year":"2010","journal-title":"PLoS Comput Biol"},{"key":"ref93","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/clpt.2009.295","article-title":"Trends in risks associated with new drug development: success rates for investigational drugs","volume":"87","author":"JA DiMasi","year":"2010","journal-title":"Clin Pharmacol Ther"},{"key":"ref94","doi-asserted-by":"crossref","first-page":"e1000441","DOI":"10.1371\/journal.pcbi.1000441","article-title":"Harvesting candidate genes responsible for serious adverse drug reactions from a chemical-protein interactome","volume":"5","author":"L Yang","year":"2009","journal-title":"PLoS Comput Biol"},{"key":"ref95","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/cmdc.200700026","article-title":"Analysis of pharmacology data and the prediction of adverse drug reactions and off-target effects from chemical structure","volume":"2","author":"A Bender","year":"2007","journal-title":"ChemMedChem"},{"key":"ref96","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/msb.2013.10","article-title":"Systematic identification of proteins that elicit drug side effects","volume":"9","author":"M Kuhn","year":"2013","journal-title":"Mol Syst Biol"},{"key":"ref97","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.amjmed.2007.09.016","article-title":"Meta-analysis: metformin treatment in persons at risk for diabetes mellitus","volume":"121","author":"SR Salpeter","year":"2008","journal-title":"Am J Med"},{"key":"ref98","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.2337\/dc08-2175","article-title":"New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes","volume":"32","author":"G Libby","year":"2009","journal-title":"Diabetes Care"},{"key":"ref99","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1471-2407-11-20","article-title":"Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals","volume":"11","author":"MS Lee","year":"2011","journal-title":"BMC Cancer"},{"key":"ref100","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1097\/FPC.0b013e3283559b22","article-title":"Metformin pathways: pharmacokinetics and pharmacodynamics","volume":"22","author":"L Gong","year":"2012","journal-title":"Pharmacogenet Genomics"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.tem.2013.05.004","article-title":"Repositioning metformin for cancer prevention and treatment","volume":"24","author":"BJ Quinn","year":"2013","journal-title":"Trends Endocrinol Metab"},{"key":"ref102","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrendo.2013.256","article-title":"Metformin\u2014mode of action and clinical implications for diabetes and cancer","volume":"10","author":"I Pernicova","year":"2014","journal-title":"Nat Rev Endocrinol"},{"key":"ref103","doi-asserted-by":"crossref","first-page":"6908","DOI":"10.1038\/onc.2008.342","article-title":"LKB1; linking cell structure and tumor suppression","volume":"27","author":"AF Hezel","year":"2008","journal-title":"Oncogene"},{"key":"ref104","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.2337\/dc09-1750","article-title":"A single nucleotide polymorphism in STK11 influences insulin sensitivity and metformin efficacy in hyperinsulinemic girls with androgen excess","volume":"33","author":"A Lopez-Bermejo","year":"2010","journal-title":"Diabetes Care"},{"key":"ref105","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.2217\/14622416.9.8.1163","article-title":"Is pharmacogenomics our future? Metformin, ovulation and polymorphism of the STK11 gene in polycystic ovary syndrome","volume":"9","author":"N Goldenberg","year":"2008","journal-title":"Pharmacogenomics"},{"key":"ref106","doi-asserted-by":"crossref","first-page":"3260","DOI":"10.1073\/pnas.97.7.3260","article-title":"Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion","volume":"97","author":"HA Coller","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref107","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00125-013-3133-4","article-title":"Common variation at PPARGC1A\/B and change in body composition and metabolic traits following preventive interventions: the Diabetes Prevention Program","volume":"57","author":"PW Franks","year":"2014","journal-title":"Diabetologia"},{"key":"ref108","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.cellsig.2013.12.004","article-title":"Repression of integrin-linked kinase by antidiabetes drugs through cross-talk of PPARgamma- and AMPKalpha-dependent signaling: role of AP-2alpha and Sp1","volume":"26","author":"SS Hahn","year":"2014","journal-title":"Cell Signal"},{"key":"ref109","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/nature11005","article-title":"Systematic identification of genomic markers of drug sensitivity in cancer cells","volume":"483","author":"MJ Garnett","year":"2012","journal-title":"Nature"},{"key":"ref110","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity","volume":"483","author":"J Barretina","year":"2012","journal-title":"Nature"},{"key":"ref111","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1073\/pnas.1018854108","article-title":"Subtype and pathway specific responses to anticancer compounds in breast cancer","volume":"109","author":"LM Heiser","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref112","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1093\/nar\/gkg585","article-title":"MATCH: A tool for searching transcription factor binding sites in DNA sequences","volume":"31","author":"AE Kel","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"ref113","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1093\/bioinformatics\/btq064","article-title":"GOSemSim: an R package for measuring semantic similarity among GO terms and gene products","volume":"26","author":"G Yu","year":"2010","journal-title":"Bioinformatics"},{"key":"ref114","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/msb.2011.47","article-title":"A pharmacogenomic method for individualized prediction of drug sensitivity","volume":"7","author":"AL Cohen","year":"2011","journal-title":"Mol Syst Biol"},{"key":"ref115","first-page":"5","article-title":"Evaluation of analytical methods for connectivity map data","author":"J Cheng","year":"2013","journal-title":"Pac Symp Biocomput"},{"key":"ref116","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1039\/c1mb05014a","article-title":"Relating protein adduction to gene expression changes: a systems approach","volume":"7","author":"B Zhang","year":"2011","journal-title":"Mol Biosyst"},{"key":"ref117","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ygeno.2011.12.005","article-title":"GenRev: exploring functional relevance of genes in molecular networks","volume":"99","author":"S Zheng","year":"2012","journal-title":"Genomics"},{"key":"ref118","article-title":"Relevant subgraph extraction from random walks in a graph","author":"P Dupont","year":"2006","journal-title":"Research report UCL\/FSA\/INGI 2006\u201307"},{"key":"ref119","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1136\/amiajnl-2011-000439","article-title":"Use of diverse electronic medical record systems to identify genetic risk for type 2 diabetes within a genome-wide association study","volume":"19","author":"AN Kho","year":"2012","journal-title":"J Am Med Inform Assoc"},{"key":"ref120","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.ajhg.2010.03.003","article-title":"Robust replication of genotype-phenotype associations across multiple diseases in an electronic medical record","volume":"86","author":"MD Ritchie","year":"2010","journal-title":"Am J Hum Genet"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/clpt.2008.89","article-title":"Development of a large-scale de-identified DNA biobank to enable personalized medicine","volume":"84","author":"DM Roden","year":"2008","journal-title":"Clin Pharmacol Ther"},{"key":"ref122","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ng1847","article-title":"Principal components analysis corrects for stratification in genome-wide association studies","volume":"38","author":"AL Price","year":"2006","journal-title":"Nat Genet"},{"key":"ref123","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1093\/bioinformatics\/btm108","article-title":"GenABEL: an R library for genome-wide association analysis","volume":"23","author":"YS Aulchenko","year":"2007","journal-title":"Bioinformatics"},{"key":"ref124","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Y Benjamini","year":"1995","journal-title":"J R Statist Soc B"},{"key":"ref125","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/nature06244","article-title":"The human microbiome project","volume":"449","author":"PJ Turnbaugh","year":"2007","journal-title":"Nature"},{"key":"ref126","doi-asserted-by":"crossref","first-page":"W741","DOI":"10.1093\/nar\/gki475","article-title":"WebGestalt: an integrated system for exploring gene sets in various biological contexts","volume":"33","author":"B Zhang","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"ref127","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"W Huang da","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"ref128","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1093\/bioinformatics\/btq675","article-title":"Cytoscape 2.8: new features for data integration and network visualization","volume":"27","author":"ME Smoot","year":"2011","journal-title":"Bioinformatics"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1007141","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T00:00:00Z","timestamp":1560470400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1004202","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,9]],"date-time":"2024-06-09T11:22:29Z","timestamp":1717932149000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1004202"}},"subtitle":[],"editor":[{"given":"Xianghong Jasmine","family":"Zhou","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2015,6,17]]},"references-count":128,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2015,6,17]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1004202","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,17]]}}}