title: Notch3 expression correlates with thyroid cancer differentiation, induces apoptosis, and predicts disease prognosis.
abstract: Thyroid tumorigenesis is characterized by a progressive loss of differentiation exhibited by a range of disease variants. The Notch receptor family (1-4) 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.
  
  
  
  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.
  
  
  
  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-of-function FTC line led to functional activation of centromere-binding protein 1, while increasing thyroid-specific gene transcription. NICD3 induction also reduced tumor burden in vivo and initiated the intrinsic apoptotic cascade, alongside suppressing cyclin and B-cell lymphoma 2 family expression.
  
  
  
  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. Cancer 2017;123:769-82. © 2016 American Cancer Society.
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Yash R
authors.initials: YR
authors.lastname: Somnay
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Yu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Ricardo V
authors.initials: RV
authors.lastname: Lloyd
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Glen
authors.initials: G
authors.lastname: Leverson
authors.affiliation: Department of Surgery, University of Alabama-Birmingham, Birmingham, Alabama.
authors.forename: Zviadi
authors.initials: Z
authors.lastname: Aburjania
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Samuel
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Surgery, University of Alabama-Birmingham, Birmingham, Alabama.
authors.forename: Renata
authors.initials: R
authors.lastname: Jaskula-Sztul
authors.affiliation: Department of Surgery, University of Alabama-Birmingham, Birmingham, Alabama.
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001706:Biopsy; D063646:Carcinogenesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D011379:Prognosis; D000071656:Receptor, Notch3 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000145:classification / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3
keywords: Notch; Notch3; anaplastic thyroid cancer; follicular thyroid cancer; papillary thyroid cancer