Purpose: Notch1, a trans-membrane receptor, has been recently shown to aid in the determination of thyroid cell fate associated with tumorigenesis. The present study aimed to investigate the clinical relevance of Notch1 and its role in the regulation of differentiated thyroid cancer (DTC) behavior. Experimental design: 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. Results: Notch1 expression levels were down-regulated in primary DTC tissue samples compared with contralateral non-tumor 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.SERPINE1 was discovered by microarray as the most significant gene down-regulated by NICD. Further validation showed that induction of NICD reduced SERPINE1 expression in a dose-dependent manner while restoration of a relative higher level of SERPINE1was observed with NICD back to minimal level. Additionally, SERPINE1 knock-down inhibited DTC cell migration. Conclusions: 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.
- Received July 24, 2015.
- Revision received December 8, 2015.
- Accepted January 18, 2016.
- Copyright © 2016, American Association for Cancer Research.