{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:00:29Z","timestamp":1790312429880,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,11,2]],"date-time":"2016-11-02T00:00:00Z","timestamp":1478044800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 GM07215"],"award-info":[{"award-number":["T32 GM07215"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000043","name":"American Association for Cancer Research","doi-asserted-by":"publisher","award":["Caring for Carcinoid Foundation Grant"],"award-info":[{"award-number":["Caring for Carcinoid Foundation Grant"]}],"id":[{"id":"10.13039\/100000043","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["Medical Student Research Fellowship"],"award-info":[{"award-number":["Medical Student Research Fellowship"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["MEN2 Thyroid Cancer Professorship 120319\u2010RPM\u201011\u201008"],"award-info":[{"award-number":["MEN2 Thyroid Cancer Professorship 120319\u2010RPM\u201011\u201008"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["Research Scholar Award RSGM TBE\u2010121413"],"award-info":[{"award-number":["Research Scholar Award RSGM TBE\u2010121413"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>Thyroid tumorigenesis is characterized by a progressive loss of differentiation exhibited by a range of disease variants. The Notch receptor family (1\u20104) regulates developmental progression in both normal and cancerous tissues. This study sought to characterize the third Notch isoform (Notch3) across the various differentiated states of thyroid cancer, and determine its clinical impact.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Notch3 expression was analyzed in a tissue microarray of normal and pathologic thyroid biopsies from 155 patients. The functional role of Notch3 was then investigated by upregulating its expression in a follicular thyroid cancer (FTC) cell line.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Notch3 expression regressed across decreasingly differentiated, increasingly malignant thyroid specimens, correlated with clinicopathological attributes reflecting poor prognosis, and independently predicted survival following univariate and multivariate analyses. Overexpression of the active Notch3 intracellular domain (NICD3) in a gain\u2010of\u2010function FTC line led to functional activation of centromere\u2010binding protein 1, while increasing thyroid\u2010specific gene transcription. NICD3 induction also reduced tumor burden in vivo and initiated the intrinsic apoptotic cascade, alongside suppressing cyclin and B\u2010cell lymphoma 2 family expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Loss of Notch3 expression may be fundamental to the process of dedifferentiation that accompanies thyroid oncogenesis. Conversely, activation of Notch3 in thyroid cancer exerts an antiproliferative effect and restores elements of a differentiated phenotype. These findings provide preclinical rationale for evaluating Notch3 as a disease prognosticator and therapeutic target in advanced thyroid cancer. <jats:bold><jats:italic>Cancer<\/jats:italic> 2017;123:769\u201382.<\/jats:bold> \u00a9 <jats:italic>2016 American Cancer Society<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.30403","type":"journal-article","created":{"date-parts":[[2016,11,2]],"date-time":"2016-11-02T13:36:59Z","timestamp":1478093819000},"page":"769-782","source":"Crossref","is-referenced-by-count":29,"title":["Notch3 expression correlates with thyroid cancer differentiation, induces apoptosis, and predicts disease prognosis"],"prefix":"10.1002","volume":"123","author":[{"given":"Yash R.","family":"Somnay","sequence":"first","affiliation":[{"name":"Department of Surgery University of Wisconsin School of Medicine and Public Health Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Min","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Wisconsin School of Medicine and Public Health Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo V.","family":"Lloyd","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen","family":"Leverson","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Wisconsin School of Medicine and Public Health Madison Wisconsin"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zviadi","family":"Aburjania","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Alabama\u2013Birmingham Birmingham 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