Intracellular calprotectin (S100A8/A9) controls epithelial differentiation and caspase-mediated cleavage of EGFR in head and neck squamous cell carcinoma
Autor: | Betty Pakzad, Ketan Patel, Mark C. Herzberg, Deepak Kademani, Ali Khammanivong, Ioannis G. Koutlas, Chris Malz, Prokopios P. Argyris, Zachary M. Slama |
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Rok vydání: | 2018 |
Předmět: |
Adult
Male Cancer Research Cellular differentiation Apoptosis medicine.disease_cause Article S100A8 03 medical and health sciences Young Adult 0302 clinical medicine Cell Line Tumor Carcinoma medicine Calgranulin B Humans Calgranulin A Epidermal growth factor receptor RNA Small Interfering 030223 otorhinolaryngology Aged Aged 80 and over Caspase 7 biology business.industry Caspase 3 Squamous Cell Carcinoma of Head and Neck Mouth Mucosa Cell Differentiation Epithelial Cells Middle Aged medicine.disease Head and neck squamous-cell carcinoma ErbB Receptors Survival Rate Oncology Head and Neck Neoplasms 030220 oncology & carcinogenesis Gene Knockdown Techniques Proteolysis Cancer research biology.protein Immunohistochemistry Female Oral Surgery Calprotectin business Carcinogenesis Leukocyte L1 Antigen Complex |
Zdroj: | Oral Oncol |
ISSN: | 1879-0593 |
Popis: | Objectives Calprotectin (S100A8/A9) appears to function as a tumor suppressor in head and neck squamous cell carcinoma (HNSCC) and expression in the carcinoma cells and patient survival rates are directly related. We seek to characterize the suppressive role of calprotectin in HNSCC. Aims (1) Investigate changes in S100A8/A9 expression as oral carcinogenesis progresses and (2) determine whether intracellular calprotectin can regulate epidermal growth factor receptor (EGFR), a negative prognostic factor, in HNSCC. Materials and methods Using immunohistochemistry (IHC), S100A8/A9 was analyzed in HNSCC specimens (N = 46), including well-differentiated (WD, N = 19), moderately-differentiated (MD, N = 14), poorly-differentiated (PD, N = 5) and non-keratinizing/basaloid (NK/BAS, N = 8), and premalignant epithelial dysplasias (PED, N = 16). Similarly, EGFR was analyzed in HNSCCs (N = 21). To determine whether calprotectin and EGFR expression are mechanistically linked, TR146 HNSCC cells that are S100A8/A9-expressing or silenced (shRNA) were compared for EGFR levels and caspase-3/7 activity using western blotting and immunofluorescence microscopy. Results In normal oral mucosal epithelium, S100A8/A9 stained strongly in the cytoplasm and nucleus of suprabasal cells; basal cells were consistently S100A8/A9 negative. In PED and HNSCC, S100A8/A9 expression was lower than in adjacent normal epithelial tissues (NAT) and declined progressively in WD, MD, PD and NK/BAS HNSCCs. S100A8/A9 and EGFR levels appeared inversely related, which was simulated in vitro when S100A8/A9 was silenced in TR146 cells. Silencing S100A8/A9 significantly reduced caspase-3/7 activity, whereas EGFR levels increased. Conclusions In HNSCC, S100A8/A9 is directly associated with cellular differentiation and appears to promote caspase-3/7-mediated cleavage of EGFR, which could explain why patients with S100A8/A9-high tumors survive longer. |
Databáze: | OpenAIRE |
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