{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T04:31:53Z","timestamp":1721622713904},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2013,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Gene expression signatures have been commonly used as diagnostic and prognostic markers for cancer subtyping. However, expression signatures frequently include many <jats:italic>passengers<\/jats:italic>, which are not directly related to cancer progression. Their upstream regulators such as transcription factors (TFs) may take a more critical role as <jats:italic>drivers<\/jats:italic> or master regulators to provide better clues on the underlying regulatory mechanisms and therapeutic applications.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In order to identify prognostic master regulators, we took the known 85 prognostic signature genes for colorectal cancer and inferred their upstream TFs. To this end, a global transcriptional regulatory network was constructed with total &gt;200,000 TF-target links using the ARACNE algorithm. We selected the top 10 TFs as candidate master regulators to show the highest coverage of the signature genes among the total 846 TF-target sub-networks or regulons. The selected TFs showed a comparable or slightly better prognostic performance than the original 85 signature genes in spite of greatly reduced number of marker genes from 85 to 10. Notably, these TFs were selected solely from inferred regulatory links using gene expression profiles and included many TFs regulating tumorigenic processes such as proliferation, metastasis, and differentiation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our network approach leads to the identification of the upstream transcription factors for prognostic signature genes to provide leads to their regulatory mechanisms. We demonstrate that our approach could identify upstream biomarkers for a given set of signature genes with markedly smaller size and comparable performances. The utility of our method may be expandable to other types of signatures such as diagnosis and drug response.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-7-86","type":"journal-article","created":{"date-parts":[[2013,9,4]],"date-time":"2013-09-04T08:15:15Z","timestamp":1378282515000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of upstream regulators for prognostic expression signature genes in colorectal cancer"],"prefix":"10.1186","volume":"7","author":[{"given":"Taejeong","family":"Bae","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoohyoung","family":"Rho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Woo","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuhisa","family":"Horimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wankyu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunghoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,9,4]]},"reference":[{"key":"1144_CR1","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/nrc2173","volume":"7","author":"C Sotiriou","year":"2007","unstructured":"Sotiriou C, Piccart MJ: Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care?. Nat Rev Cancer. 2007, 7: 545-53. 10.1038\/nrc2173.","journal-title":"Nat Rev Cancer"},{"key":"1144_CR2","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.1158\/1078-0432.CCR-10-0175","volume":"17","author":"E M\u00e9ndez","year":"2011","unstructured":"M\u00e9ndez E, Lohavanichbutr P, Fan W, Houck JR, Rue TC, Doody DR, Futran ND, Upton MP, Yueh B, Zhao LP, Schwartz SM, Chen C: Can a metastatic gene expression profile outperform tumor size as a predictor of occult lymph node metastasis in oral cancer patients?. Clin Cancer Res. 2011, 17: 2466-73. 10.1158\/1078-0432.CCR-10-0175.","journal-title":"Clin Cancer Res"},{"key":"1144_CR3","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1158\/1078-0432.CCR-11-1954","volume":"45","author":"N Servant","year":"2012","unstructured":"Servant N, Bollet MA, Halfwerk H, Bleakley K, Kreike B, Jacob L, Sie D, Kerkhoven R, Hupe P, Hadhri R, Fourquet A, Bartelink H, Barillot E, Sigal-Zafrani B, Van De Vijver M: Search for a gene expression signature of breast cancer local recurrence in young women. Clin Cancer Res. 2012, 45: 1704-15.","journal-title":"Clin Cancer Res"},{"key":"1144_CR4","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1038\/415530a","volume":"415","author":"LJ Van Veer","year":"2002","unstructured":"Van Veer LJ, Dai H, Van De Vijver MJ, Schreiber GJ, Kerkhoven RM, Roberts C, Bernards \u00c2, Friend SH, Linsley PS:Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415: 530-6. 10.1038\/415530a.","journal-title":"Nature"},{"key":"1144_CR5","doi-asserted-by":"publisher","first-page":"2817","DOI":"10.1056\/NEJMoa041588","volume":"351","author":"S Paik","year":"2004","unstructured":"Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004, 351: 2817-26. 10.1056\/NEJMoa041588.","journal-title":"N Engl J Med"},{"key":"1144_CR6","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/nrg2137","volume":"8","author":"JR Nevins","year":"2007","unstructured":"Nevins JR, Potti A: Mining gene expression profiles: expression signatures as cancer phenotypes. Nat Rev Genet. 2007, 8: 601-9.","journal-title":"Nat Rev Genet"},{"key":"1144_CR7","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1016\/j.cell.2011.03.001","volume":"144","author":"D Pe\u2019er","year":"2011","unstructured":"Pe\u2019er D, Hacohen N: Principles and strategies for developing network models in cancer. Cell. 2011, 144: 864-73. 10.1016\/j.cell.2011.03.001.","journal-title":"Cell"},{"key":"1144_CR8","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1038\/nature08712","volume":"463","author":"MS Carro","year":"2010","unstructured":"Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H, Lasorella A, Aldape K, Califano A, Iavarone A: The transcriptional network for mesenchymal transformation of brain tumours. Nature. 2010, 463: 318-25. 10.1038\/nature08712.","journal-title":"Nature"},{"key":"1144_CR9","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/nprot.2006.106","volume":"1","author":"A Margolin","year":"2006","unstructured":"Margolin A, Wang K, Lim WK, Kustagi M, Nemenman I, Califano A: Reverse engineering cellular networks. Nat Protoc. 2006, 1: 662-71. 10.1038\/nprot.2006.106.","journal-title":"Nat Protoc"},{"key":"1144_CR10","doi-asserted-by":"publisher","first-page":"69","DOI":"10.3322\/caac.20107","volume":"61","author":"A Jemal","year":"2011","unstructured":"Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322\/caac.20107.","journal-title":"CA Cancer J Clin"},{"key":"1144_CR11","doi-asserted-by":"publisher","first-page":"7642","DOI":"10.1158\/1078-0432.CCR-09-1431","volume":"15","author":"RN Jorissen","year":"2009","unstructured":"Jorissen RN, Gibbs P, Christie M, Prakash S, Lipton L, Desai J, Kerr D, Aaltonen LA, Arango D, Kruh\u00f8ffer M, Orntoft TF, Andersen CL, Gruidl M, Kamath VP, Eschrich S, Yeatman TJ, Sieber OM: Metastasis-associated gene expression changes predict poor outcomes in patients with Dukes Stage B and C colorectal cancer. Clin Cancer Res. 2009, 15: 7642-51. 10.1158\/1078-0432.CCR-09-1431.","journal-title":"Clin Cancer Res"},{"key":"1144_CR12","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1053\/j.gastro.2009.11.005","volume":"138","author":"JJ Smith","year":"2010","unstructured":"Smith JJ, Deane NG, Wu F, Merchant NB, Zhang B, Jiang A, Lu P, Johnson JC, Schmidt C, Bailey CE, Eschrich S, Kis C, Levy S, Washington MK, Heslin MJ, Coffey RJ, Yeatman TJ, Shyr Y, Beauchamp RD: Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology. 2010, 138: 958-68. 10.1053\/j.gastro.2009.11.005.","journal-title":"Gastroenterology"},{"key":"1144_CR13","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1007\/s00109-009-0467-y","volume":"87","author":"E Staub","year":"2009","unstructured":"Staub E, Groene J, Heinze M, Mennerich D, Roepcke S, Klaman I, Hinzmann B, Castanos-Velez E, Pilarsky C, Mann B, Br\u00fcmmendorf T, Weber B, Buhr H-J, Rosenthal A: An expression module of WIPF1-coexpressed genes identifies patients with favorable prognosis in three tumor types. J Mol Med. 2009, 87: 633-44. 10.1007\/s00109-009-0467-y.","journal-title":"J Mol Med"},{"key":"1144_CR14","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1136\/gutjnl-2011-300812","volume":"61","author":"SC Oh","year":"2012","unstructured":"Oh SC, Park Y-Y, Park ES, Lim JY, Kim SM, Kim S-B, Kim J, Kim SC, Chu I-S, Smith JJ, Beauchamp RD, Yeatman TJ, Kopetz S, Lee J-S: Prognostic gene expression signature associated with two molecularly distinct subtypes of colorectal cancer. Gut. 2012, 61: 1291-8. 10.1136\/gutjnl-2011-300812.","journal-title":"Gut"},{"key":"1144_CR15","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/cdd.2008.21","volume":"15","author":"EB Rankin","year":"2008","unstructured":"Rankin EB, Giaccia a J: The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008, 15: 678-85. 10.1038\/cdd.2008.21.","journal-title":"Cell Death Differ"},{"key":"1144_CR16","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.molcel.2010.09.022","volume":"40","author":"AJ Majmundar","year":"2010","unstructured":"Majmundar AJ, Wong WJ, Simon MC: Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010, 40: 294-309. 10.1016\/j.molcel.2010.09.022.","journal-title":"Mol Cell"},{"key":"1144_CR17","doi-asserted-by":"publisher","first-page":"2292","DOI":"10.2353\/ajpath.2010.090972","volume":"176","author":"Y Baba","year":"2010","unstructured":"Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, Chung DC, Giovannucci EL, Fuchs CS, Ogino S: HIF1A Overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol. 2010, 176: 2292-301. 10.2353\/ajpath.2010.090972.","journal-title":"Am J Pathol"},{"key":"1144_CR18","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1476-4598-5-56","volume":"5","author":"J Pan","year":"2006","unstructured":"Pan J, Mestas J, Burdick MD, Phillips RJ, Thomas GV, Reckamp K, Belperio J a, Strieter RM: Stromal derived factor-1 (SDF-1\/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Mol Cancer. 2006, 5: 56-10.1186\/1476-4598-5-56.","journal-title":"Mol Cancer"},{"key":"1144_CR19","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1038\/nature04695","volume":"440","author":"JT Erler","year":"2006","unstructured":"Erler JT, Bennewith KL, Nicolau M, Dornh\u00f6fer N, Kong C, Le Q-T, Chi J-TA, Jeffrey SS, Giaccia AJ: Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006, 440: 1222-6. 10.1038\/nature04695.","journal-title":"Nature"},{"key":"1144_CR20","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1002\/ijc.20438","volume":"112","author":"H Zhong","year":"2004","unstructured":"Zhong H, Willard M, Simons J: NS398 reduces hypoxia-inducible factor (HIF)-1alpha and HIF-1 activity: multiple-level effects involving cyclooxygenase-2 dependent and independent mechanisms. Int J Cancer. 2004, 112: 585-95. 10.1002\/ijc.20438.","journal-title":"Int J Cancer"},{"key":"1144_CR21","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1182\/blood.V94.3.959.415k20_959_967","volume":"94","author":"PA Outinen","year":"1999","unstructured":"Outinen PA, Sood SK, Pfeifer SI, Pamidi S, Podor TJ, Li J, Weitz JI, Austin RC: Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood. 1999, 94: 959-67.","journal-title":"Blood"},{"key":"1144_CR22","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1161\/CIRCULATIONAHA.109.855114","volume":"120","author":"B Maurer","year":"2009","unstructured":"Maurer B, Busch N, J\u00fcngel A, Pileckyte M, Gay RE, Michel BA, Schett G, Gay S, Distler J, Distler O: Transcription factor fos-related antigen-2 induces progressive peripheral vasculopathy in mice closely resembling human systemic sclerosis. Circulation. 2009, 120: 2367-76. 10.1161\/CIRCULATIONAHA.109.855114.","journal-title":"Circulation"},{"key":"1144_CR23","doi-asserted-by":"publisher","first-page":"2900","DOI":"10.1182\/blood-2004-09-3630","volume":"105","author":"SF Landrette","year":"2005","unstructured":"Landrette SF, Kuo Y-H, Hensen K, van Waalwijk B, van Doorn-Khosrovani S, Perrat PN, Van de Ven WJM, Delwel R, Castilla LH: Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. Blood. 2005, 105: 2900-7. 10.1182\/blood-2004-09-3630.","journal-title":"Blood"},{"key":"1144_CR24","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.lungcan.2011.02.006","volume":"74","author":"Y-S Yang","year":"2011","unstructured":"Yang Y-S, Yang M-CW, Weissler JC: Pleiomorphic adenoma gene-like 2 expression is associated with the development of lung adenocarcinoma and emphysema. Lung cancer. 2011, 74: 12-24. 10.1016\/j.lungcan.2011.02.006.","journal-title":"Lung cancer"},{"key":"1144_CR25","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.ccr.2010.03.020","volume":"17","author":"H Zheng","year":"2010","unstructured":"Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV, Paik J-H, Zhang H, Xiao Y, Perry SR, Hu J, Vinjamoori A, Gan B, Sahin E, Chheda MG, Brennan C, Wang YA, Hahn WC, Chin L, DePinho RA: PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer cell. 2010, 17: 497-509. 10.1016\/j.ccr.2010.03.020.","journal-title":"Cancer cell"},{"key":"1144_CR26","doi-asserted-by":"publisher","first-page":"4718","DOI":"10.1038\/sj.onc.1204647","volume":"20","author":"T Furukawa","year":"2001","unstructured":"Furukawa T, Adachi Y, Fujisawa J, Kambe T, Yamaguchi-Iwai Y, Sasaki R, Kuwahara J, Ikehara S, Tokunaga R, Taketani S: Involvement of PLAGL2 in activation of iron deficient- and hypoxia-induced gene expression in mouse cell lines. Oncogene. 2001, 20: 4718-27. 10.1038\/sj.onc.1204647.","journal-title":"Oncogene"},{"key":"1144_CR27","doi-asserted-by":"publisher","first-page":"15851","DOI":"10.1074\/jbc.M111431200","volume":"277","author":"A Mizutani","year":"2002","unstructured":"Mizutani A, Furukawa T, Adachi Y, Ikehara S, Taketani S: A zinc-finger protein, PLAGL2, induces the expression of a proapoptotic protein Nip3, leading to cellular apoptosis. J Biol Chem. 2002, 277: 15851-8. 10.1074\/jbc.M111431200.","journal-title":"J Biol Chem"},{"key":"1144_CR28","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1007\/s10495-011-0672-3","volume":"17","author":"TS Hanks","year":"2012","unstructured":"Hanks TS, Gauss KA: Pleomorphic adenoma gene-like 2 regulates expression of the p53 family member, p73, and induces cell cycle block and apoptosis in human promonocytic U937 cells. Apoptosis. 2012, 17: 236-47. 10.1007\/s10495-011-0672-3.","journal-title":"Apoptosis"},{"key":"1144_CR29","doi-asserted-by":"publisher","first-page":"3445","DOI":"10.1038\/sj.onc.1209382","volume":"25","author":"AM Jubb","year":"2006","unstructured":"Jubb AM, Chalasani S, Frantz GD, Smits R, Grabsch HI, Kavi V, Maughan NJ, Hillan KJ, Quirke P, Koeppen H: Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia. Oncogene. 2006, 25: 3445-57. 10.1038\/sj.onc.1209382.","journal-title":"Oncogene"},{"key":"1144_CR30","doi-asserted-by":"publisher","first-page":"e32170","DOI":"10.1371\/journal.pone.0032170","volume":"7","author":"R Zhu","year":"2012","unstructured":"Zhu R, Yang Y, Tian Y, Bai J, Zhang X, Li X, Peng Z, He Y, Chen L, Pan Q, Fang D, Chen W, Qian C, Bian X, Wang R: Ascl2 knockdown results in tumor growth arrest by miRNA-302b-related inhibition of colon cancer progenitor cells. PloS one. 2012, 7: e32170-10.1371\/journal.pone.0032170.","journal-title":"PloS one"},{"key":"1144_CR31","doi-asserted-by":"publisher","first-page":"1923","DOI":"10.1126\/science.285.5435.1923","volume":"285","author":"J Roose","year":"1999","unstructured":"Roose J: Synergy between tumor suppressor APC and the -catenin-Tcf4 target Tcf1. Science. 1999, 285: 1923-26. 10.1126\/science.285.5435.1923.","journal-title":"Science"},{"key":"1144_CR32","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1023\/A:1025858928620","volume":"23","author":"ML Waterman","year":"2004","unstructured":"Waterman ML: Lymphoid enhancer factor\/T cell factor expression in colorectal cancer. Cancer Metastasis Rev. 2004, 23: 41-52.","journal-title":"Cancer Metastasis Rev"},{"key":"1144_CR33","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1182\/blood.V94.2.741","volume":"94","author":"T Nakamura","year":"1999","unstructured":"Nakamura T, Yamazaki Y, Hatano Y, Miura I: NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15). Blood. 1999, 94: 741-7.","journal-title":"Blood"},{"key":"1144_CR34","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1002\/jcb.22371","volume":"108","author":"O Moussa","year":"2009","unstructured":"Moussa O, Turner DP, Feldman RJ, Sementchenko VI, McCarragher BD, Desouki MM, Fraig M, Watson DK: PDEF is a negative regulator of colon cancer cell growth and migration. J Cell Biochem. 2009, 108: 1389-98. 10.1002\/jcb.22371.","journal-title":"J Cell Biochem"},{"key":"1144_CR35","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.canlet.2011.06.011","volume":"310","author":"JJ Steffan","year":"2011","unstructured":"Steffan JJ, Koul HK: Prostate derived ETS factor (PDEF): a putative tumor metastasis suppressor. Cancer letters. 2011, 310: 109-17. 10.1016\/j.canlet.2011.06.011.","journal-title":"Cancer letters"},{"key":"1144_CR36","first-page":"289","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995, 57: 289-300.","journal-title":"J R Stat Soc B"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-7-86.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T01:31:56Z","timestamp":1630546316000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-7-86"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,4]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,12]]}},"alternative-id":["1144"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-7-86","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9,4]]},"assertion":[{"value":"23 April 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2013","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 September 2013","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"86"}}