{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T11:00:52Z","timestamp":1782990052745,"version":"3.54.5"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2014,10,1]],"date-time":"2014-10-01T00:00:00Z","timestamp":1412121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000191","name":"Kidney Foundation of Canada","doi-asserted-by":"publisher","award":["KFOC130030"],"award-info":[{"award-number":["KFOC130030"]}],"id":[{"id":"10.13039\/501100000191","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000109","name":"Prostate Cancer Canada","doi-asserted-by":"publisher","award":["D2013-39"],"award-info":[{"award-number":["D2013-39"]}],"id":[{"id":"10.13039\/501100000109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>The outcome of clear cell renal cell carcinoma (ccRCC) is still unpredictable. Even with new targeted therapies, the average progression-free survival is dismal. Markers for early detection and progression could improve disease outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>To identify efficient and hitherto unrecognized pathogenic factors of the disease, we performed a uniquely comprehensive pathway analysis and built a gene interaction network based on large publicly available data sets assembled from 28 publications, comprising a 3-prong approach with high-throughput mRNA, microRNA, and protein expression profiles of 593 ccRCC and 389 normal kidney samples. We validated our results on 2 different data sets of 882 ccRCC and 152 normal tissues. Functional analyses were done by proliferation, migration, and invasion assays following siRNA (small interfering RNA) knockdown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>After integration of multilevel data, we identified aryl-hydrocarbon receptor (AHR), grainyhead-like-2 (GRHL2), and KIAA0101 as new pathogenic factors. GRHL2 expression was associated with higher chances for disease relapse and retained prognostic utility after controlling for grade and stage [hazard ratio (HR), 3.47, P = 0.012]. Patients with KIAA0101-positive expression suffered worse disease-free survival (HR, 3.64, P &amp;lt; 0.001), and in multivariate analysis KIAA0101 retained its independent prognostic significance. Survival analysis showed that GRHL2- and KIAA0101-positive patients had significantly lower disease-free survival (P = 0.002 and P &amp;lt; 0.001). We also found that KIAA0101 silencing decreased kidney cancer cell migration and invasion in vitro.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>Using an integrative system biology approach, we identified 3 novel factors as potential biomarkers (AHR, GRHL2 and KIAA0101) involved in ccRCC pathogenesis and not linked to kidney cancer before.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1373\/clinchem.2014.225854","type":"journal-article","created":{"date-parts":[[2014,8,19]],"date-time":"2014-08-19T23:30:50Z","timestamp":1408491050000},"page":"1314-1326","source":"Crossref","is-referenced-by-count":51,"title":["Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma"],"prefix":"10.1093","volume":"60","author":[{"given":"Henriett","family":"Butz","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M","family":"Szab\u00f3","sequence":"first","affiliation":[{"name":"Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Nofech-Mozes","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Rotondo","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalman","family":"Kovacs","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorna","family":"Mirham","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"Girgis","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina","family":"Boles","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Patocs","sequence":"first","affiliation":[{"name":"HAS-SE \u201cLendulet\u201d Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George M","family":"Yousef","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and the Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,10,1]]},"reference":[{"key":"2020022705525317200_B1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3233\/CBM-2011-0176","article-title":"Renal cell carcinoma","volume":"9","author":"Cairns","year":"2010","journal-title":"Cancer Biomark"},{"key":"2020022705525317200_B2","article-title":"Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis","author":"Vera-Badillo","journal-title":"Eur Urol"},{"key":"2020022705525317200_B3","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.prp.2013.01.007","article-title":"Renal tumors with clear cells. A review","volume":"209","author":"Lopez","year":"2013","journal-title":"Pathol Res Pract"},{"key":"2020022705525317200_B4","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1056\/NEJMoa1113205","article-title":"Intratumor heterogeneity and branched evolution revealed by multiregion sequencing","volume":"366","author":"Gerlinger","year":"2012","journal-title":"N Engl J Med"},{"key":"2020022705525317200_B5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1186\/1479-5876-11-169","article-title":"Clear cell renal cell carcinoma associated microRNA expression signatures identified by an integrated bioinformatics analysis","volume":"11","author":"Chen","year":"2013","journal-title":"J Transl Med"},{"key":"2020022705525317200_B6","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1158\/0008-5472.CAN-11-1698","article-title":"Integrative genomic analyses of sporadic clear cell renal cell carcinoma define disease subtypes and potential new therapeutic targets","volume":"72","author":"Dondeti","year":"2012","journal-title":"Cancer Res"},{"key":"2020022705525317200_B7","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/ng.2699","article-title":"Integrated molecular analysis of clear-cell renal cell carcinoma","volume":"45","author":"Sato","year":"2013","journal-title":"Nat Genet"},{"key":"2020022705525317200_B8","doi-asserted-by":"crossref","first-page":"719","DOI":"10.3892\/ol.2011.294","article-title":"EPAS1 mRNA in plasma from colorectal cancer patients is associated with poor outcome in advanced stages","volume":"2","author":"Mohammed","year":"2011","journal-title":"Oncol Lett"},{"key":"2020022705525317200_B9","doi-asserted-by":"crossref","first-page":"e61196","DOI":"10.1371\/journal.pone.0061196","article-title":"p15(PAF) is an Rb\/E2F-regulated S-phase protein essential for DNA synthesis and cell cycle progression","volume":"8","author":"Chang","year":"2013","journal-title":"PLoS One"},{"key":"2020022705525317200_B10","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1093\/carcin\/bgt184","article-title":"miR-192, miR-194 and miR-215: a convergent microRNA network suppressing tumor progression in renal cell carcinoma","volume":"34","author":"Khella","year":"2013","journal-title":"Carcinogenesis"},{"key":"2020022705525317200_B11","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":"Vidal","year":"2011","journal-title":"Cell"},{"key":"2020022705525317200_B12","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/msb.2009.52","article-title":"Genomic analysis reveals a tight link between transcription factor dynamics and regulatory network architecture","volume":"5","author":"Jothi","year":"2009","journal-title":"Mol Syst Biol"},{"key":"2020022705525317200_B13","doi-asserted-by":"crossref","first-page":"e44459","DOI":"10.1371\/journal.pone.0044459","article-title":"Control centrality and hierarchical structure in complex networks","volume":"7","author":"Liu","year":"2012","journal-title":"PLoS One"},{"key":"2020022705525317200_B14","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.ymgme.2010.06.005","article-title":"Pathway analysis software: annotation errors and solutions","volume":"101","author":"Henderson-Maclennan","year":"2010","journal-title":"Mol Genet Metab"},{"key":"2020022705525317200_B15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1089\/omi.2008.0060","article-title":"Interlaboratory and interplatform comparison of microarray gene expression analysis of HepG2 cells exposed to benzo (a) pyrene","volume":"13","author":"Hockley","year":"2009","journal-title":"OMICS"},{"key":"2020022705525317200_B16","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.ab.2006.03.023","article-title":"Strategies for comparing gene expression profiles from different microarray platforms: application to a case-control experiment","volume":"353","author":"Severgnini","year":"2006","journal-title":"Anal Biochem"},{"key":"2020022705525317200_B17","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/ki.2013.245","article-title":"Renal cell carcinoma: translational aspects of metabolism and therapeutic consequences","volume":"84","author":"Yang","year":"2013","journal-title":"Kidney Int"},{"key":"2020022705525317200_B18","doi-asserted-by":"crossref","first-page":"3582","DOI":"10.1016\/j.febslet.2011.10.025","article-title":"Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR","volume":"585","author":"Huang","year":"2011","journal-title":"FEBS Lett"},{"key":"2020022705525317200_B19","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1515\/BC.2006.145","article-title":"A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis","volume":"387","author":"Schlezinger","year":"2006","journal-title":"Biol Chem"},{"key":"2020022705525317200_B20","first-page":"1194","article-title":"The aryl hydrocarbon receptor: studies using the AHR-null mice","volume":"26","author":"Gonzalez","year":"1998","journal-title":"Drug Metab Dispos"},{"key":"2020022705525317200_B21","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1515\/bc.2010.128","article-title":"An introduction to the molecular basics of aryl hydrocarbon receptor biology","volume":"391","author":"Abel","year":"2010","journal-title":"Biol Chem"},{"key":"2020022705525317200_B22","doi-asserted-by":"crossref","first-page":"3263","DOI":"10.1091\/mbc.e08-04-0359","article-title":"The aryl hydrocarbon receptor binds to E2F1 and inhibits E2F1-induced apoptosis","volume":"19","author":"Marlowe","year":"2008","journal-title":"Mol Biol Cell"},{"key":"2020022705525317200_B23","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1093\/carcin\/bgp222","article-title":"Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer","volume":"31","author":"Ishida","year":"2010","journal-title":"Carcinogenesis"},{"key":"2020022705525317200_B24","first-page":"125","article-title":"Aryl hydrocarbon receptor activation by aminoflavone: new molecular target for renal cancer treatment","volume":"41","author":"Callero","year":"2012","journal-title":"Int J Oncol"},{"key":"2020022705525317200_B25","first-page":"725","article-title":"Development of cardiac hypertrophy by sunitinib in vivo and in vitro rat cardiomyocytes is influenced by the aryl hydrocarbon receptor signaling pathway","volume":"88","author":"Maayah","year":"2013","journal-title":"Arch Toxicol"},{"key":"2020022705525317200_B26","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1111\/j.1349-7006.2006.00268.x","article-title":"Expression of Ets-1 in human clear cell renal cell carcinomas: implications for angiogenesis","volume":"97","author":"Mikami","year":"2006","journal-title":"Cancer Sci"},{"key":"2020022705525317200_B27","doi-asserted-by":"crossref","first-page":"6299","DOI":"10.1158\/0008-5472.CAN-12-4082","article-title":"Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2","volume":"73","author":"Cieply","year":"2013","journal-title":"Cancer Res"},{"key":"2020022705525317200_B28","doi-asserted-by":"crossref","first-page":"e450","DOI":"10.1038\/cddis.2012.190","article-title":"Grainyhead-like 2 (GRHL2) inhibits keratinocyte differentiation through epigenetic mechanism","volume":"3","author":"Chen","year":"2012","journal-title":"Cell Death Dis"},{"key":"2020022705525317200_B29","doi-asserted-by":"crossref","first-page":"e50781","DOI":"10.1371\/journal.pone.0050781","article-title":"Grhl2 determines the epithelial phenotype of breast cancers and promotes tumor progression","volume":"7","author":"Xiang","year":"2012","journal-title":"PLoS One"},{"key":"2020022705525317200_B30","doi-asserted-by":"crossref","first-page":"9845","DOI":"10.1073\/pnas.1106136108","article-title":"Proliferating cell nuclear antigen (PCNA)-associated KIAA0101\/PAF15 protein is a cell cycle-regulated anaphase-promoting complex\/cyclosome substrate","volume":"108","author":"Emanuele","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020022705525317200_B31","doi-asserted-by":"crossref","first-page":"e26866","DOI":"10.1371\/journal.pone.0026866","article-title":"KIAA0101 is overexpressed, and promotes growth and invasion in adrenal cancer","volume":"6","author":"Jain","year":"2011","journal-title":"PLoS One"},{"key":"2020022705525317200_B32","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1158\/0008-5472.CAN-07-2491","article-title":"In vivo switching of human melanoma cells between proliferative and invasive states","volume":"68","author":"Hoek","year":"2008","journal-title":"Cancer Res"},{"key":"2020022705525317200_B33","doi-asserted-by":"crossref","first-page":"2681","DOI":"10.1007\/s13277-013-1353-3","article-title":"KIAA0101 mRNA overexpression in peripheral blood mononuclear cells acts as predictive marker for hepatic cancer","volume":"35","author":"Su","year":"2013","journal-title":"Tumour Biol"},{"key":"2020022705525317200_B34","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1741-7015-6-15","article-title":"MicroRNAs: regulators of oncogenesis and stemness","volume":"6","author":"Papagiannakopoulos","year":"2008","journal-title":"BMC Med"},{"key":"2020022705525317200_B35","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3892\/ijmm.2013.1365","article-title":"Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L","volume":"32","author":"Zhao","year":"2013","journal-title":"Int J Mol Med"},{"key":"2020022705525317200_B36","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1002\/stem.490","article-title":"miR-124a is important for migratory cell fate transition during gastrulation of human embryonic stem cells","volume":"28","author":"Lee","year":"2010","journal-title":"Stem Cells"},{"key":"2020022705525317200_B37","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1158\/0008-5472.CAN-12-2895","article-title":"Loss of miR-204 expression enhances glioma migration and stem cell-like phenotype","volume":"73","author":"Ying","year":"2013","journal-title":"Cancer Res"},{"key":"2020022705525317200_B38","doi-asserted-by":"crossref","first-page":"687","DOI":"10.2353\/jmoldx.2010.090187","article-title":"Accurate molecular classification of renal tumors using microRNA expression","volume":"12","author":"Fridman","year":"2010","journal-title":"J Mol Diagn"},{"key":"2020022705525317200_B39","doi-asserted-by":"crossref","first-page":"e35661","DOI":"10.1371\/journal.pone.0035661","article-title":"Identification of a 4-microRNA signature for clear cell renal cell carcinoma metastasis and prognosis","volume":"7","author":"Wu","year":"2012","journal-title":"PLoS One"},{"key":"2020022705525317200_B40","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1053\/j.gastro.2011.08.050","article-title":"HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells","volume":"141","author":"Bao","year":"2011","journal-title":"Gastroenterology"},{"key":"2020022705525317200_B41","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1002\/cbf.2902","article-title":"Derepression of c-Fos caused by microRNA-139 down-regulation contributes to the metastasis of human hepatocellular carcinoma","volume":"31","author":"Fan","year":"2013","journal-title":"Cell Biochem Funct"}],"container-title":["Clinical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/60\/10\/1314\/32663530\/clinchem1314.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/60\/10\/1314\/32663530\/clinchem1314.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T05:54:14Z","timestamp":1582782854000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/clinchem\/article\/60\/10\/1314\/5621663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,1]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2014,10,1]]},"published-print":{"date-parts":[[2014,10,1]]}},"URL":"https:\/\/doi.org\/10.1373\/clinchem.2014.225854","relation":{},"ISSN":["0009-9147","1530-8561"],"issn-type":[{"value":"0009-9147","type":"print"},{"value":"1530-8561","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,10,1]]},"published":{"date-parts":[[2014,10,1]]}}}