title: Notch1 Signaling Regulates the Aggressiveness of Differentiated Thyroid Cancer and Inhibits SERPINE1 Expression.
abstract: Notch1, a transmembrane receptor, has been recently shown to aid in the determination of thyroid cell fate associated with tumorigenesis. This study aimed to investigate the clinical relevance of Notch1 and its role in the regulation of differentiated thyroid cancer (DTC) behavior.
  
  
  
  We examined Notch1 expression level and its relationship with clinicopathologic features and outcomes of DTC. Notch1 intracellular domain (NICD) was further characterized both in vitro and in vivo by gain-of-function assays using an inducible system.
  
  
  
  Notch1 expression levels were downregulated in primary DTC tissue samples compared with contralateral nontumor and benign thyroid tissues. Decreased Notch1 expression in DTC was associated with advanced patient age (P = 0.032) and the presence of extrathyroidal invasion (P = 0.005). Patients with lower Notch1 expression had a significantly higher recurrence rate (P = 0.038). Restoration of NICD in a stably doxycycline-inducible metastatic DTC cell line reduced cell growth and migration profoundly. Using an orthotopic thyroid cancer model, NICD induction significantly reduced the growth of the primary thyroid tumor and inhibited the development of lung metastasis. Serpin peptidase inhibitor, clade E, member 1 (SERPINE1) was discovered by microarray as the most significant gene downregulated by NICD. Further validation showed that the induction of NICD reduced SERPINE1 expression in a dose-dependent manner, whereas restoration of a relative higher level of SERPINE1 was observed with NICD back to minimal level. In addition, SERPINE1 knock-down inhibited DTC cell migration.
  
  
  
  Notch1 regulates the aggressive phenotypes of DTC, which could be mediated by SERPINE1 inhibition. Notch1/SERPINE1 axis warrants further investigation as a novel therapeutic target for advanced DTC. Clin Cancer Res; 22(14); 3582-92. ©2016 AACR.
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. jessica.xm.yu@gmail.com herbchen@uab.edu.
authors: Xiao-Min
authors: XM
authors: Yu
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Renata
authors: R
authors: Jaskula-Sztul
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Maria R
authors: MR
authors: Georgen
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Zviadi
authors: Z
authors: Aburjania
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Yash R
authors: YR
authors: Somnay
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Glen
authors: G
authors: Leverson
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Rebecca S
authors: RS
authors: Sippel
authors: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Ricardo V
authors: RV
authors: Lloyd
authors: Department of Biomedical Engineering, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors: Brian P
authors: BP
authors: Johnson
authors: Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama. jessica.xm.yu@gmail.com herbchen@uab.edu.
authors: Herbert
authors: H
authors: Chen
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000378:metabolism*
chemical_list: C497761:NOTCH1 protein, human; D017395:Plasminogen Activator Inhibitor 1; D051881:Receptor, Notch1; C051321:SERPINE1 protein, human