Activation of Mammalian Target of Rapamycin Pathway Confers Adverse Outcome in Nonsmall Cell Lung Carcinoma
Activation of Mammalian Target of Rapamycin Pathway Confers Adverse Outcome in Nonsmall Cell Lung Carcinoma
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DOI：
10.1002/cncr.25959
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发表时间：
2011-08-15
期刊：
影响因子：
6.2
通讯作者：
Li, Weimin
中科院分区：
文献类型：
--
作者：
Liu, Dan;Huang, Yi;Li, Weimin
背景：哺乳动物雷帕霉素靶蛋白（mTOR）通路的失调已被证明有助于肿瘤的发生。本研究旨在探讨mTOR通路在非小细胞肺癌（NSCLC）患者中的蛋白表达谱及其与预后的关系。方法：免疫组化法检测mTOR/磷酸化（p-）mTOR、磷酸肌醇依赖性激酶1（PDK 1）/p-PDK 1、p-Akt 1和P70核糖体蛋白S6激酶（P70 S6 K）/p-P70 S6 K的蛋白表达谱。采用单因素和多因素生存分析研究单个和联合蛋白表达的临床预后价值。研究结果：与正常肺组织相比，肿瘤组织中mTOR/p-mTOR、p-Akt 1 Ser 473/Thr 308、P70 S6 K/p-P70 S6 K蛋白表达水平均升高（P均<0.05），而p-PDK 1蛋白表达水平降低（P <0.05）。p-mTOR表达与组织分化、组织学类型、淋巴结浸润和分期有关（均P <0.05）。在p-mTOR、p-PDK 1和p-P70 S6 K阳性表型的NSCLC患者中，总生存期显著较短（均P <0.05）。p-mTOR、p-PDK 1、p-Akt 1 Ser 473和p-P70 S6 K中任意2种共表达的受试者的预后比不表达生物标志物或仅表达任意1种生物标志物的受试者差（均P <0.05）。多因素分析显示p-mTOR/p-P70 S6 K联合表达是除肿瘤分期外的独立预后因素。结论：这项研究提供了临床证据，表明mTOR通路的活化组分，而不是总蛋白，是NSCLC预后不良的预测因子。此外，评估这些分子的蛋白质表达谱可能是NSCLC个体化治疗的新策略。Cancer 2011;117：3763-73. (C)2011年美国癌症协会
BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. Cancer 2011;117:3763-73. (C) 2011 American Cancer Society.