Nikitakis Nikolaos G, Scheper Mark A, Papanikolaou Vasileios S, Sauk John J
Department of Oral Pathology and Medicine, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 Jun;107(6):826-36. doi: 10.1016/j.tripleo.2008.12.054. Epub 2009 Mar 9.
Constitutive activation of the signal transducer and activator of transcription 3 (Stat3) has been detected in various human cancers and has been linked to tumor development and progression. Oncogenic Stat3 signaling results in induction of specific target genes, among which survivin is implicated in the proliferation and survival of cancer cells. Targeting of Stat3 constitutive expression by the nonsteroidal antiinflammatory drug (NSAID) sulindac has been demonstrated to exert antineoplastic effects in oral squamous cell carcinoma cells in vitro and in vivo.
The expression and functional role of Stat3 and survivin was evaluated in 2 salivary gland adenocarcinoma cell lines (HSY and HSG). In addition, the effects of the NSAID sulindac and other cyclooxygenase (COX) inhibitors on Stat3 and survivin expression and on cell proliferation and apoptosis of HSY and HSG cells were analyzed.
Messenger RNA and protein expression of Stat3 and survivin was detected in HSY and HSG cell lines. Treatment of these cells with siRNA against Stat3 or survivin inhibited cell proliferation and induced apoptosis. Moreover, Stat3 siRNA treatment down-regulated the protein and mRNA expression of survivin, and survivin forced expression partially reversed the antineoplastic effects of Stat3 siRNA treatment. Treatment of HSY and HSG cells with the NSAID sulindac, but not other COX inhibitors, induced significant decreases in cell proliferation and increases in apoptosis, accompanied by down-regulation of Stat3 and survivin expression. In contrast, survivin forced expression or transfection with constitutively active Stat3 attenuated the effects of sulindac on cell growth and apoptosis.
Taken together, these data support the importance of the constitutive Stat3 signaling for growth and survival of salivary gland cancer cells through the induction of survivin. Inhibition of the oncogenic Stat3-survivin pathway in these cells can be achieved by selective targeting techniques or treatment with the NSAID sulindac and holds promise for the treatment of salivary gland cancer.
在多种人类癌症中均检测到信号转导及转录激活因子3（Stat3）的组成性激活，且其与肿瘤的发生发展相关。致癌性Stat3信号传导会诱导特定靶基因的表达，其中survivin与癌细胞的增殖和存活有关。非甾体抗炎药（NSAID）舒林酸靶向Stat3组成性表达已被证明在体外和体内对口腔鳞状细胞癌细胞具有抗肿瘤作用。
评估Stat3和survivin在2种唾液腺腺癌细胞系（HSY和HSG）中的表达及功能作用。此外，分析了NSAID舒林酸和其他环氧化酶（COX）抑制剂对HSY和HSG细胞中Stat3和survivin表达以及细胞增殖和凋亡的影响。
在HSY和HSG细胞系中检测到Stat3和survivin的信使核糖核酸及蛋白表达。用针对Stat3或survivin的小干扰RNA（siRNA）处理这些细胞可抑制细胞增殖并诱导凋亡。此外，Stat3 siRNA处理下调了survivin的蛋白和信使核糖核酸表达，而survivin的强制表达部分逆转了Stat3 siRNA处理的抗肿瘤作用。用NSAID舒林酸而非其他COX抑制剂处理HSY和HSG细胞，可导致细胞增殖显著减少和凋亡增加，同时伴有Stat3和survivin表达下调。相反，survivin的强制表达或用组成性激活的Stat3转染可减弱舒林酸对细胞生长和凋亡的影响。
综上所述，这些数据支持组成性Stat3信号传导通过诱导survivin对唾液腺癌细胞的生长和存活具有重要意义。通过选择性靶向技术或用NSAID舒林酸处理可抑制这些细胞中的致癌性Stat3-survivin途径，这为唾液腺癌的治疗带来了希望。
