Notch activation leads to loss of myoepithelial differentiation and poor outcome in solid adenoid cystic carcinoma

Oral Diseases
Ye ZhangTie-Jun Li

Abstract

We aimed to investigate Notch pathway dysregulation in solid adenoid cystic carcinoma (AdCC) and to define the association of Notch activation with cell differentiation and prognosis in AdCCs. Notch1 mutations were detected from 125 AdCCs (62 cribriform-tubular; 63 solid). RNA-seq was performed in 16 AdCCs (6 Notch-mutant; 10 wild type). Notch activation indicator NICD and myoepithelial marker p63 were detected using immunohistochemistry and double-labelling immunofluorescence. The effect of exogenous NICD overexpression on p63 expression and cell proliferation was investigated using Western blotting and live-cell imaging. We identified 33 Notch1 activating mutations in 27 AdCCs including 26 solid and 1 cribriform-tubular subtypes. Six tumours harboured more than one Notch1 mutation, and 18 Notch1 mutations were novel. Most (47/63, 74.6%) solid AdCCs showed NICD overexpression, whereas 61 of 62 (98.4%) cribriform-tubular tumours were negative. NICD and p63 exhibited mutually exclusive expression, and exogenous NICD overexpression promoted cell proliferation and decreased p63 expression. NICD overexpression and Notch mutations were poor indicators for overall survival and metastasis, especially bone metastasis. Dysregulated Notc...Continue Reading

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