{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T08:54:57Z","timestamp":1776416097523,"version":"3.51.2"},"reference-count":38,"publisher":"Portland Press Ltd.","issue":"4","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":387,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,8,31]]},"abstract":"<jats:p>Uveal melanoma (UM) is the most common primary intraocular tumor in adults, and it carries a high risk of metastasis and mortality. Various proinflammatory cytokines have been found to be significantly increased in the aqueous humor or vitreous fluid of UM patients; however, the role of these cytokines in UM metastasis remains elusive. In the present study, we found that long-term interleukin (IL)-6 exposure promoted the migration and invasion of UM cells, diminished cell\u2013cell adhesion, and enhanced focal adhesion. Moreover, IL-6 treatment decreased the membranous epithelial marker TJP1 and increased the cytoplasmic mesenchymal marker Vimentin. Further investigation demonstrated that JunB played a critical role in IL-6-induced UM epithelial\u2013mesenchymal transition (EMT). In UM cells, the expression of JunB was significantly up-regulated during the IL-6-driven EMT process. Additionally, JunB induction occurred at the transcriptional level in a manner dependent on phosphorylated STAT3, during which activated STAT3 directly bound to the JunB promoter. Importantly, the knockdown of STAT3 prevented the IL-6-induced EMT phenotype as well as cell migration and invasion, whereas JunB overexpression recovered the attenuated aggressiveness of UM cells. Similarly, with IL-6 stimulation, the stable overexpression of JunB strengthened the migratory and invasive capabilities of UM cells and induced the EMT-promoting factors (Snail, Twist1, matrix metalloproteinase (MMP)-2, MMP-14, and MMP-19). Analysis of The Cancer Genome Atlas (TCGA) database indicated that JunB was positively correlated with IL-6 and STAT3 in UM tissues. The present study proposes an IL-6\/STAT3\/JunB axis leading to UM aggressiveness by EMT, which illustrates the negative side of inflammatory response in UM metastasis.<\/jats:p>","DOI":"10.1042\/bsr20180532","type":"journal-article","created":{"date-parts":[[2018,6,13]],"date-time":"2018-06-13T22:20:20Z","timestamp":1528928420000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Abnormally expressed JunB transactivated by IL-6\/STAT3 signaling promotes uveal melanoma aggressiveness via epithelial\u2013mesenchymal transition"],"prefix":"10.1042","volume":"38","author":[{"given":"Chaoju","family":"Gong","sequence":"first","affiliation":[{"name":"Xuzhou Key Laboratory of Ophthalmology, The Municipal Affiliated Hospital of Xuzhou Medical University, Eye Institute of Xuzhou, Xuzhou 221002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Nursing, The Municipal Affiliated Hospital of Xuzhou Medical University, Eye Institute of Xuzhou, Xuzhou 221002,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zejun","family":"Fang","sequence":"additional","affiliation":[{"name":"Central Laboratory, Sanmen People\u2019s Hospital of Zhejiang, Sanmen 317100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Qiao","sequence":"additional","affiliation":[{"name":"Xuzhou Key Laboratory of Ophthalmology, The Municipal Affiliated Hospital of Xuzhou Medical University, Eye Institute of Xuzhou, Xuzhou 221002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruifang","family":"Feng","sequence":"additional","affiliation":[{"name":"Xuzhou Key Laboratory of Ophthalmology, The Municipal Affiliated Hospital of Xuzhou Medical University, Eye Institute of Xuzhou, Xuzhou 221002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianmi","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Sanmen People\u2019s Hospital of Zhejiang, Sanmen 317100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suyan","family":"Li","sequence":"additional","affiliation":[{"name":"Xuzhou Key Laboratory of Ophthalmology, The Municipal Affiliated Hospital of Xuzhou Medical University, Eye Institute of Xuzhou, Xuzhou 221002, China"},{"name":"Department of Ophthalmology, The Municipal Affiliated Hospital of Xuzhou Medical University, Eye Institute of Xuzhou, Xuzhou 221002,China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2018,7,3]]},"reference":[{"key":"2021111618595935000_B1","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/sj.bjc.6605765","article-title":"Does ocular treatment of uveal melanoma influence survival?","volume":"103","author":"Damato","year":"2010","journal-title":"Br. J. Cancer"},{"key":"2021111618595935000_B2","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.ajo.2009.01.023","article-title":"Effectiveness of treatments for metastatic uveal melanoma","volume":"148","author":"Augsburger","year":"2009","journal-title":"Am. J. Ophthalmol."},{"key":"2021111618595935000_B3","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1093\/carcin\/bgp127","article-title":"Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability","volume":"30","author":"Colotta","year":"2009","journal-title":"Carcinogenesis"},{"key":"2021111618595935000_B4","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1007\/s00262-010-0968-0","article-title":"2011: the immune hallmarks of cancer","volume":"60","author":"Cavallo","year":"2011","journal-title":"Cancer Immunol. Immunother."},{"key":"2021111618595935000_B5","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3109\/09273941003669950","article-title":"Influence of immune privilege on ocular tumor development","volume":"18","author":"McKenna","year":"2010","journal-title":"Ocul. Immunol. Inflamm."},{"key":"2021111618595935000_B6","doi-asserted-by":"publisher","first-page":"5529","DOI":"10.1167\/iovs.10-6331","article-title":"Effects of interleukin-1 receptor antagonist on tumor stroma in experimental uveal melanoma","volume":"52","author":"Triozzi","year":"2011","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2021111618595935000_B7","doi-asserted-by":"publisher","first-page":"5445","DOI":"10.1167\/iovs.10-5526","article-title":"Inflammatory cytokines in eyes with uveal melanoma and relation with macrophage infiltration","volume":"51","author":"Ly","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2021111618595935000_B8","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1097\/IAE.0b013e318239e299","article-title":"Intraocular activation of angiogenic and inflammatory pathways in uveal melanoma","volume":"32","author":"Dunavoelgyi","year":"2012","journal-title":"Retina"},{"key":"2021111618595935000_B9","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1046\/j.1523-1747.2003.12417.x","article-title":"Tumor necrosis factor alpha increases and alpha-melanocyte-stimulating hormone reduces uveal melanoma invasion through fibronectin","volume":"121","author":"Canton","year":"2003","journal-title":"J. Invest. Dermatol."},{"key":"2021111618595935000_B10","doi-asserted-by":"publisher","first-page":"6748","DOI":"10.1167\/iovs.12-10123","article-title":"Cytokines and chemokines in the vitreous fluid of eyes with uveal melanoma","volume":"53","author":"Nagarkatti-Gude","year":"2012","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2021111618595935000_B11","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/nrc1209","article-title":"AP-1: a double-edged sword in tumorigenesis","volume":"3","author":"Eferl","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"2021111618595935000_B12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/sj.onc.1209759","article-title":"Transcription factors control invasion: AP-1 the first among equals","volume":"26","author":"Ozanne","year":"2007","journal-title":"Oncogene"},{"key":"2021111618595935000_B13","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/ng790","article-title":"JunB can substitute for Jun in mouse development and cell proliferation","volume":"30","author":"Passegue","year":"2002","journal-title":"Nat. Genet."},{"key":"2021111618595935000_B14","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1083\/jcb.201109045","article-title":"JunB contributes to Id2 repression and the epithelial-mesenchymal transition in response to transforming growth factor-beta","volume":"196","author":"Gervasi","year":"2012","journal-title":"J. Cell Biol."},{"key":"2021111618595935000_B15","doi-asserted-by":"publisher","first-page":"2514","DOI":"10.1093\/nar\/gkw126","article-title":"Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition","volume":"44","author":"Chang","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2021111618595935000_B16","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s13046-016-0284-4","article-title":"JunB promotes cell invasion, migration and distant metastasis of head and neck squamous cell carcinoma","volume":"35","author":"Hyakusoku","year":"2016","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"2021111618595935000_B17","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1007\/s10585-011-9449-x","article-title":"Regulation of HGF-mediated cell proliferation and invasion through NF-kappaB, JunB, and MMP-9 cascades in stomach cancer cells","volume":"29","author":"Lee","year":"2012","journal-title":"Clin. Exp. Metastasis"},{"key":"2021111618595935000_B18","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.5858\/2009-0441-RAR.1","article-title":"Ocular melanoma","volume":"134","author":"Laver","year":"2010","journal-title":"Arch. Pathol. Lab. Med."},{"key":"2021111618595935000_B19","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s40259-016-0167-4","article-title":"Update on metastatic uveal melanoma: progress and challenges","volume":"30","author":"Spagnolo","year":"2016","journal-title":"BioDrugs"},{"key":"2021111618595935000_B20","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41598-017-00079-x","article-title":"ZEB1 regulates multiple oncogenic components involved in uveal melanoma progression","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"2021111618595935000_B21","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1007\/s12253-009-9150-4","article-title":"Zonula occludens-1, occludin, and E-cadherin protein expression in biliary tract cancers","volume":"15","author":"Nemeth","year":"2009","journal-title":"Pathol. Oncol. Res."},{"key":"2021111618595935000_B22","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s10120-008-0497-0","article-title":"Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival","volume":"12","author":"Ohtani","year":"2009","journal-title":"Gastric Cancer"},{"key":"2021111618595935000_B23","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.1016\/j.ejca.2004.08.008","article-title":"Loss of tight junction plaque molecules in breast cancer tissues is associated with a poor prognosis in patients with breast cancer","volume":"40","author":"Martin","year":"2004","journal-title":"Eur. J. Cancer"},{"key":"2021111618595935000_B24","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3390\/jcm5020026","article-title":"Homeostatic signaling by cell-cell junctions and its dysregulation during cancer progression","volume":"5","author":"Yu","year":"2016","journal-title":"J. Clin. Med."},{"key":"2021111618595935000_B25","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1016\/j.bbamem.2008.08.027","article-title":"Cytokine regulation of tight junctions","volume":"1788","author":"Capaldo","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"2021111618595935000_B26","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/978-3-319-42023-3_4","article-title":"Cell-ECM interactions in tumor invasion","volume":"936","author":"He","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"2021111618595935000_B27","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1038\/sj.eye.6701471","article-title":"Invasive and noninvasive uveal melanomas have different adhesive properties","volume":"19","author":"Woodward","year":"2005","journal-title":"Eye"},{"key":"2021111618595935000_B28","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/eye.1999.79","article-title":"The correlation between cell surface markers and clinical features in choroidal malignant melanomas","volume":"13","author":"Lawry","year":"1999","journal-title":"Eye"},{"key":"2021111618595935000_B29","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1159\/000012083","article-title":"Expression of the cell adhesion molecules ICAM-1, VCAM-1 and NCAM in uveal melanoma: a clinicopathological study","volume":"58","author":"Anastassiou","year":"2000","journal-title":"Oncology"},{"key":"2021111618595935000_B30","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/cr.2008.18","article-title":"STAT3 as a target for inducing apoptosis in solid and hematological tumors","volume":"18","author":"Al Zaid Siddiquee","year":"2008","journal-title":"Cell Res."},{"key":"2021111618595935000_B31","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1016\/j.ejca.2005.08.008","article-title":"The Fos family of transcription factors and their role in tumourigenesis","volume":"41","author":"Milde-Langosch","year":"2005","journal-title":"Eur. J. Cancer"},{"key":"2021111618595935000_B32","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/0092-8674(89)90755-1","article-title":"jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun","volume":"59","author":"Schutte","year":"1989","journal-title":"Cell"},{"key":"2021111618595935000_B33","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3892\/ijo.2014.2761","article-title":"Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2\/STAT3\/Snail pathway","volume":"46","author":"Fu","year":"2015","journal-title":"Int. J. Oncol."},{"key":"2021111618595935000_B34","doi-asserted-by":"publisher","first-page":"8617","DOI":"10.1158\/0008-5472.CAN-06-1308","article-title":"Regulation of transforming growth factor-beta 1-induced apoptosis and epithelial-to-mesenchymal transition by protein kinase A and signal transducers and activators of transcription 3","volume":"66","author":"Yang","year":"2006","journal-title":"Cancer Res."},{"key":"2021111618595935000_B35","first-page":"919","article-title":"EMT-associated factors promote invasive properties of uveal melanoma cells","volume":"21","author":"Asnaghi","year":"2015","journal-title":"Mol. Vis."},{"key":"2021111618595935000_B36","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.canlet.2017.04.028","article-title":"In vitro and in vivo anti-uveal melanoma activity of JSL-1, a novel HDAC inhibitor","volume":"400","author":"Wang","year":"2017","journal-title":"Cancer Lett."},{"key":"2021111618595935000_B37","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1167\/iovs.15-18780","article-title":"Protein tyrosine phosphatase 4A3 (PTP4A3) promotes human uveal melanoma aggressiveness through membrane accumulation of matrix metalloproteinase 14 (MMP14)","volume":"57","author":"Maacha","year":"2016","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"2021111618595935000_B38","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/modpathol.2009.183","article-title":"MMP19 is upregulated during melanoma progression and increases invasion of melanoma cells","volume":"23","author":"Muller","year":"2010","journal-title":"Mod. Pathol."}],"updated-by":[{"DOI":"10.1042\/bsr-2018-0532_ret","type":"retraction","label":"Retraction","source":"retraction-watch","updated":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"record-id":"44676"},{"DOI":"10.1042\/bsr-2018-0532_ret","type":"retraction","label":"Retraction","source":"publisher","updated":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000}}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20180532\/480016\/bsr-2018-0532.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20180532\/480016\/bsr-2018-0532.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T19:43:07Z","timestamp":1637091787000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/38\/4\/BSR20180532\/57930\/Abnormally-expressed-JunB-transactivated-by-IL-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,3]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,8,31]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20180532","relation":{"retraction":[{"id-type":"doi","id":"10.1042\/BSR-2018-0532_RET","asserted-by":"object"}]},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"value":"0144-8463","type":"print"},{"value":"1573-4935","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,3]]},"article-number":"BSR20180532"}}