Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Sci Rep. 2017 Aug 15;7(1):8178. doi: 10.1038/s41598-017-08345-8.
Despite improvement in preoperative imaging, surgical technique, and adjuvant therapy, the prognosis of patients with tongue squamous cell carcinoma (SCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) play a key role in the regulation of tumor cell proliferation and survival. However, the significance of mTOR on the prognosis of tongue SCC remains largely undefined. In the present study, immunohistochemistry was performed to evaluate the expression of phosphorylated mTOR (p-mTOR) in 160 surgically resected tongue SCC, and correlated with survival. Univariate analysis revealed that p-mTOR overexpression (P = 0.006) was associated with inferior overall survival. In multivariate comparison, p-mTOR overexpression (P = 0.002, hazard ratio = 2.082) remained independently associated with worse overall survival. In vitro study, tongue cancer cells treated with everolimus, the specific mTOR inhibitor, or transfected with mTOR-mediated siRNAs dramatically attenuated the abilities of cell proliferation by MTT and BrdU assays. In 4-NQO-induced tongue cancer murine model, mTOR inhibitors significantly decreased the incidence of tongue SCC. In conclusion, p-mTOR overexpression was independently associated with poor prognosis of patients with tongue SCC. In vitro and vivo, mTOR inhibition showed the promising activity in tongue SCC. Our results suggest that inhibition of mTOR signaling pathway may be a novel therapeutic target for tongue SCC.
尽管术前影像学、手术技术和辅助治疗有所改善，但舌鳞状细胞癌 (SCC) 患者的预后仍然不尽如人意。哺乳动物雷帕霉素靶蛋白 (mTOR) 在调节肿瘤细胞增殖和存活方面发挥着关键作用。然而，mTOR 对舌 SCC 预后的意义在很大程度上仍未得到明确。本研究通过免疫组织化学方法检测了 160 例手术切除的舌 SCC 中磷酸化 mTOR (p-mTOR) 的表达，并与生存相关联。单因素分析显示，p-mTOR 过表达（P=0.006）与总生存率降低相关。多因素比较显示，p-mTOR 过表达（P=0.002，风险比=2.082）与总生存率降低独立相关。体外研究表明，用特异性 mTOR 抑制剂依维莫司或 mTOR 介导的 siRNA 转染处理的舌癌细胞，通过 MTT 和 BrdU 检测法显著减弱了细胞增殖能力。在 4-NQO 诱导的舌癌小鼠模型中，mTOR 抑制剂显著降低了舌 SCC 的发生率。总之，p-mTOR 过表达与舌 SCC 患者的不良预后独立相关。在体外和体内，mTOR 抑制显示出在舌 SCC 中有良好的治疗活性。我们的研究结果表明，抑制 mTOR 信号通路可能是舌 SCC 的一种新的治疗靶点。
