Overexpression of the cytokine osteopontin identifies aggressive laryngeal squamous cell carcinomas and enhances carcinoma cell proliferation and invasiveness
Overexpression of the cytokine osteopontin identifies aggressive laryngeal squamous cell carcinomas and enhances carcinoma cell proliferation and invasiveness
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DOI：
10.1158/1078-0432.ccr-05-0641
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发表时间：
2005-11-15
影响因子：
11.5
通讯作者：
Santoro, M
中科院分区：
文献类型：
--
作者：
Celetti, A;Testa, D;Santoro, M
目的：骨桥蛋白是一种与细胞表面CD44v6受体结合的分泌型细胞因子。我们研究了骨桥蛋白和CD44v6在喉鳞状细胞癌中的表达及其与临床病理肿瘤特征的关系。实验设计：采用免疫组织化学、免疫印迹和逆转录-聚合酶链式反应研究58例喉鳞状细胞癌中骨桥蛋白的表达。用外源性骨桥蛋白或RNA干扰抑制体外培养的鳞癌细胞骨桥蛋白的表达。结果：骨桥蛋白在所有浸润性癌中的表达均高于患者配对的正常粘膜。其表达水平与肿瘤分期、分级、有无淋巴结转移及远处转移密切相关。骨桥蛋白阳性与总生存期呈负相关(P=0.03)。骨桥蛋白的表达与CD44v6强烈的细胞表面反应是平行的。与未处理的细胞相比，重组骨桥蛋白处理的鳞癌细胞的增殖和Matrigel侵袭能力显著增强，同时丝裂原活化蛋白激酶/细胞外信号调节激酶/丝裂原活化蛋白激酶信号通路也被激活。通过RNA干扰、抗CD44抗体和丝裂原活化蛋白激酶/细胞外信号调节激酶抑制抑制骨桥蛋白可阻止上述作用。结论：骨桥蛋白可作为侵袭性喉鳞癌的标志物和潜在的治疗靶点。
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.