Overexpression of the cytokine osteopontin identifies aggressive laryngeal squamous cell carcinomas and enhances carcinoma cell proliferation and invasiveness.
OBJECTIVE
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.


METHODS
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.
Celetti
Angela
A
Istituto di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche/Dipartimento di Biologia e Patologia Cellulare e Molecolare, University of Naples Federico II, Italy.
Testa
Domenico
D
Staibano
Stefania
S
Merolla
Francesco
F
Guarino
Valentina
V
Castellone
Maria Domenica
MD
Iovine
Renata
R
Mansueto
Gelsomina
G
Somma
Pasquale
P
De Rosa
Gaetano
G
Galli
Vieri
V
Melillo
Rosa Marina
RM
Santoro
Massimo
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002070:Butadienes / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000235:genetics; D007150:Immunohistochemistry; D007822:Laryngeal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology; D053495:Osteopontin; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000032:analysis / Q000235:genetics* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D015854:Up-Regulation
D002070:Butadienes; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D009570:Nitriles; D012333:RNA, Messenger; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C113580:U 0126; D053495:Osteopontin; D020929:Mitogen-Activated Protein Kinase Kinases