Notch1 Signaling Regulates the Aggressiveness of Differentiated Thyroid Cancer and Inhibits SERPINE1 Expression

Abstract

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.

Notch3 expression correlates with thyroid cancer differentiation, induces apoptosis, and predicts disease prognosis

“…FTC133 was selected because it exhibited high baseline Notch3 expression and was FTC236's nonmetastatic counterpart. We have previously reported that FTC133 has a slower migratory rate than that of FTC236, consistent with its relatively benign phenotype . NOTCH3 suppression significantly enhanced cell migration ( P = 7.8 × 10 −6 ; Fig.…”

The Role of Notch3 in Cancer

“…Missense mutations in the Notch1 gene causes bicuspid aortic valve formation, and its deletion is lethal during early stages of embryogenesis . It has also been shown to have both oncogenic and tumor suppressor roles in different types of cancers . Mutations in the Notch2 gene can cause Alagille and Hajdu‐Cheney syndromes, two autosomal‐dominant genetic conditions that affect skeletal, cardiovascular, neural, and gastrointestinal system development .…”

“…Changes in Notch activity have been associated with several benign and malignant diseases . Although the primary function of Notch seems to be regulation of vasculogenesis, in which its dysregulation has been linked to a number of vasculopathies, it can also have tumor suppressive or oncogenic roles (Table ).…”

The evolving concept of cancer stem-like cells in thyroid cancer and other solid tumors

“…7,[43][44][45][46][47][48][49][50] NOTCH PATHWAY Mammalian cells express four transmembrane Notch receptors including NOTCH-1, NOTCH-2, NOTCH-3 and NOTCH-4. [43][44][45][46][47][48][49][50] Notch signaling has been implicated in selfrenewal in CSCs in a variety of cancers. Notch receptors are expressed during the development of thyrocytes in experimental systems and the expression levels of these receptors are aligned with thyroid differentiation markers.…”

“…Restoration of Notch-1 intracellular domain in a stable doxycyclineinducible metastatic differentiated thyroid carcinoma cell line led to a reduction in cell growth and tumor cell migration. 47 Wnt/β-CATENIN Wnt/β-catenin or canonical Wnt pathway leads to the accumulation of β-catenin in the cell cytoplasm, which is then translocated into the nucleus and acts as a transcriptional co-activator of the TCF/LEF family of transcription factors. Experimental evidence has shown that Wnt2/2b and β-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut.…”