NOTCH1 signaling in oral squamous cell carcinoma via a TEL2/SERPINE1 axis

Abstract

Inactivating mutations in the EGF-like ligand binding domain of <i>NOTCH1</i> are a prominent feature of the mutational landscape of oral squamous cell carcinoma (OSCC). In this study, we investigated <i>NOTCH1</i> mutations in keratinocyte lines derived from OSCC biopsies that had been subjected to whole exome sequencing. One line, SJG6, was found to have truncating mutations in both <i>NOTCH1</i> alleles, resulting in loss of NOTCH1 expression. Overexpression of the NOTCH1 intracellular domain (NICD) in SJG6 cells promoted cell adhesion and differentiation, while suppressing proliferation, migration and clonal growth, consistent with the previously reported tumour suppressive function of NOTCH1 in OSCC. Comparative gene expression profiling identified <i>SERPINE1</i> as being downregulated on NICD overexpression and predicted an interaction between <i>SERPINE1</i> and genes involved in cell proliferation and migration. Mechanistically, overexpression of NICD resulted in upregulation of <i>ETV7</i>/TEL2, which negatively regulates <i>SERPINE1</i> expression. Knockdown of <i>SERPINE1</i> phenocopied the effects of NICD overexpression in culture. Consistent with previous studies and our <i>in vitro</i> findings, there were inverse correlations between <i>ETV7</i> and <i>SERPINE1</i> expression and survival in OSCC primary tumours. Our results suggest that the tumour suppressive role of <i>NOTCH1</i> in OSCC is mediated, at least in part, by inhibition of <i>SERPINE1</i> via <i>ETV7</i>.