Abstract
High-risk human papilloma virus (HR-HPV) has increasingly been associated with head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal cancers. Ezrin–Radixin–Moesin Binding Phosphoprotein 50 (EBP50), a putative tumour suppressor, localises to the plasma membrane in suprabasal epithelium and to the cytoplasm in proliferative basal layers, and is a target for degradation by the HR-HPV E6 oncoprotein. The aim of this study was to investigate EBP50 protein expression patterns in HNSCC in a large Scottish cohort to determine if there was a correlation with HPV status and clinical outcomes. EBP50 expression patterns were assessed in 156 HNSCC including oropharyngeal (37.8%), laryngeal (24%), oral (19%) and other sites (18.5%), which were genotyped for presence of HR-HPV. HNSCC were generally negative for membranous EBP50. EBP50 expression was either cytoplasmic/absent, being ‘predominantly cytoplasmic’ in 76 (49%), ‘weak/negligible cytoplasmic’ in 44 (28%), ‘strongly cytoplasmic’ in 5 (3%), ‘heterogeneous’ in 26 (17%) and ‘other’ in 5 (3%) samples. Forty tumours (25%) were positive for HPV DNA, predominantly HR-HPV 16, and 44 (28%) were p16 positive. The majority of tumours (71%) with ‘weak/negligible cytoplasmic’ EBP50 expression originated in the oropharynx were more likely to have positive neck nodes, overexpression of p16 and positive tumour HR-HPV status (P < 0.001). Differences in EBP50 levels between oropharyngeal and non-oropharyngeal tumours may be linked to degradation of EBP50 by HR-HPV, and loss of EBP50 may therefore be a surrogate biomarker for HR-HPV infection in oropharyngeal tumours.
Highlights
In 2014, there were 11,400 new cases of head and neck squamous cell carcinoma (HNSCC) in the United Kingdom and over the last decade, incidence rates have increased by almost a quarter [1]
Ezrin–Radixin–Moesin Binding Phosphoprotein 50 (EBP50) staining differed in the different layers of tonsil tissue (Fig. 1A (b)) and normal oral mucosa (Fig. 1B (b)), the staining pattern was consistent between the two tissue types
Moving deeper from the suprabasal to the stratum basale, EBP50 staining changed from the membrane to a predominantly cytoplasmic location (Fig. 1A, B (d)), which correlated with proliferative basal layers
Summary
In 2014, there were 11,400 new cases of head and neck squamous cell carcinoma (HNSCC) in the United Kingdom and over the last decade, incidence rates have increased by almost a quarter [1]. Ezrin–Radixin–Moesin (ERM) Binding Phosphoprotein 50 (EBP50), a PDZ (postsynaptic density 95, PSD-85; discs large, Dlg; zonula occludens-1, ZO-1) domain scaffolding protein, known as Na+/H+ exchanger 3 regulatory factor 1 (NHERF1), is found in abundance at the plasma membranes of polarised epithelial cells where it regulates tissue architecture and cell migration. It functions as a molecular scaffold, promoting the assembly of macromolecular signalling protein complexes at the plasma membrane of epithelial cells, thereby regulating their activity. Major signalling pathways regulated by EBP50 include Phosphatidylinositol3-OH kinase (PI-3K)/AKT/Phosphatase and tensin homologue (PTEN) pathway, platelet derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and Wnt/β-catenin signalling [3]
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