Overexpression of the Cytokine Osteopontin Identifies Aggressive Laryngeal Squamous Cell Carcinomas and Enhances Carcinoma Cell Proliferation and Invasiveness

• Published in: Clinical cancer research 2005-11, Vol.11 (22), p.8019-8027
• Main Authors: CELETTI, Angela, TESTA, Domenico, GALLI, Vieri, MELILLO, Rosa Marina, SANTORO, Massimo, STAIBANO, Stefania, MEROLLA, Francesco, GUARINO, Valentina, CASTELLONE, Maria Domenica, IOVINE, Renata, MANSUETO, Gelsomina, SOMMA, Pasquale, DE ROSA, Gaetano
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Butadienes - pharmacology; carcinoma; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; CD44; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors - pharmacology; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors - analysis; Hyaluronan Receptors - genetics; Immunohistochemistry; kinase; Laryngeal Neoplasms - genetics; Laryngeal Neoplasms - metabolism; Laryngeal Neoplasms - pathology; larynx; Male; Medical sciences; Middle Aged; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; motility; Neoplasm Invasiveness; Nitriles - pharmacology; oncogene; Osteopontin; Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sialoglycoproteins - analysis; Sialoglycoproteins - genetics; Sialoglycoproteins - pharmacology; Signal Transduction - drug effects; Survival Analysis; Tumors; Up-Regulation; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0641

Purpose: Osteopontin is a secreted cytokine that binds to the cell surface CD44v6 receptor. We studied osteopontin and CD44v6 expression in laryngeal squamous cell carcinomas and correlated osteopontin expression levels with clinicopathologic tumor features. Experimental Design: We used immunohistochemistry, immunoblotting, and reverse transcription-PCR to study osteopontin expression in 58 laryngeal squamous cell carcinomas. Cultured squamous carcinoma cells were treated with exogenous osteopontin or with RNA interference to knockdown osteopontin expression. Results: Osteopontin expression was higher in all the invasive carcinomas than in patient-matched normal mucosa. Its expression levels were significantly correlated with tumor stage and grade and with the presence of lymph node and distant metastases. Osteopontin positivity was negatively correlated with overall survival ( P = 0.03). Osteopontin expression was paralleled by intense cell surface reactivity for CD44v6. Treatment of squamous carcinoma cells with recombinant osteopontin sharply increased proliferation and Matrigel invasion in comparison with the untreated cells parallel to activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase signaling cascade. Osteopontin knockdown by RNA interference, anti-CD44 antibodies, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibition prevented these effects. Conclusions: These results identify osteopontin as a marker and a potential therapeutic target in cases of aggressive laryngeal squamous cell carcinomas.