Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
Cancer. 2011 Aug 15;117(16):3763-73. doi: 10.1002/cncr.25959. Epub 2011 Mar 8.
Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been shown to contribute to tumorigenesis. This study explored protein expression profiles of mTOR pathway and the relationship with prognosis in patients with nonsmall cell lung carcinoma (NSCLC).
The protein expression profiles of mTOR/phosphorylated (p-)mTOR, phosphoinositide-dependent kinase 1 (PDK1)/p-PDK1, p-Akt1, and P70 ribosomal protein S6 kinase (P70S6K)/p-P70S6K were determined via immunohistochemical staining assay. The clinical prognostic values of both single and combined protein expression were investigated with univariate and multivariate survival analysis.
Compared with normal lung tissues, the protein levels of mTOR/p-mTOR, p-Akt1 Ser473/Thr308, and P70S6K/p-P70S6K were higher (all P < .05), whereas p-PDK1 was lower (P < .05) in tumor tissues. p-mTOR expression was associated with histological differentiation, histological type, lymph node invasion, and stage (all P < .05). Overall survival in NSCLC patients was significantly shorter in cases with positive phenotype for p-mTOR, p-PDK1, and p-P70S6K (all P < .05). Subjects with coexpression of any 2 of p-mTOR, p-PDK1, p-Akt1 Ser473, and p-P70S6K demonstrated worse prognosis than those expressing no biomarker or any 1 biomarker alone (all P < .05). Multivariate analysis showed that the combination of p-mTOR/p-P70S6K is an independent prognostic factor in addition to tumor stage.
This study provides clinical evidence that activated components of mTOR pathway, not total protein, are predictors of poor prognosis in NSCLC. Moreover, evaluating protein-expression profiles of these molecules might be a new strategy for individual therapy in subjects with NSCLC.
哺乳动物雷帕霉素靶蛋白（mTOR）通路的失调已被证明与肿瘤发生有关。本研究探讨了 mTOR 通路的蛋白表达谱及其与非小细胞肺癌（NSCLC）患者预后的关系。
采用免疫组织化学染色法检测 mTOR/磷酸化（p-）mTOR、磷酸肌醇依赖性激酶 1（PDK1）/p-PDK1、p-Akt1 Ser473/Thr308 和 P70 核糖体蛋白 S6 激酶（P70S6K）/p-P70S6K 的蛋白表达谱。采用单因素和多因素生存分析研究了单一和联合蛋白表达的临床预后价值。
与正常肺组织相比，肿瘤组织中 mTOR/p-mTOR、p-Akt1 Ser473/Thr308 和 P70S6K/p-P70S6K 的蛋白水平较高（均 P <.05），而 p-PDK1 的蛋白水平较低（P <.05）。p-mTOR 的表达与组织学分化、组织学类型、淋巴结浸润和分期有关（均 P <.05）。p-mTOR、p-PDK1 和 p-P70S6K 阳性表型的 NSCLC 患者总生存期明显缩短（均 P <.05）。同时表达 2 种或 2 种以上 p-mTOR、p-PDK1、p-Akt1 Ser473 和 p-P70S6K 的患者预后比不表达或仅表达 1 种生物标志物的患者更差（均 P <.05）。多因素分析显示，除肿瘤分期外，p-mTOR/p-P70S6K 联合表达是独立的预后因素。
本研究为 mTOR 通路激活成分而非总蛋白是 NSCLC 患者不良预后的预测因子提供了临床证据。此外，评估这些分子的蛋白表达谱可能是 NSCLC 患者个体化治疗的新策略。
