Phosphorylated mTOR Expression is Associated with Poor Prognosis for Patients with Esophageal Squamous Cell Carcinoma
Phosphorylated mTOR Expression is Associated with Poor Prognosis for Patients with Esophageal Squamous Cell Carcinoma
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DOI：
10.1245/s10434-010-1040-1
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发表时间：
2010-09-01
影响因子：
3.7
通讯作者：
Baba, Hideo
中科院分区：
文献类型：
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作者：
Hirashima, Kotaro;Baba, Yoshifumi;Baba, Hideo
背景哺乳动物雷帕霉素靶蛋白（mTOR）通过监测营养物质的可利用性、细胞能量水平、氧水平和促有丝分裂信号在细胞生长和增殖的调节中起核心作用。已经在几种类型的癌症中报道了与临床结果相关的mTOR的异常激活。mTOR作为抗癌治疗的潜在靶点越来越重要。尽管如此，食管鳞状细胞癌（ESCC）中mTOR激活的预后特征仍不确定。首先，为了验证磷酸化特异性mTOR抗体（Ser 2448），通过体外免疫组织化学和免疫印迹法评估了在有或没有依维莫司（mTOR抑制剂，也称为RAD 001）的培养条件下五种ESCC细胞系中磷酸化mTOR（p-mTOR）的表达水平。其次，我们使用143例切除的ESCC标本通过免疫组化检测p-mTOR表达。通过考克斯回归分析和Kaplan-Meier分析检测p-mTOR表达的预后意义。在143例患者中，71例（49.7%）被归类为p-mTOR阳性，72例（50.3%）被归类为p-mTOR阴性。与p-mTOR阴性患者相比，p-mTOR阳性患者的总体死亡率较高[风险比（HR）2.44; 95%置信区间（CI），1.24-4.83; P = 0.008]，在多变量分析中持续存在（多变量HR 2.92; 95% CI，1.48-5.78; P = 0.002）。食管癌特异性死亡率也观察到类似的结果。p-mTOR表达与年龄、性别、肿瘤部位、组织学分级、手术方式、T分期（肿瘤浸润）、淋巴结转移等临床病理变量无关。p-mTOR过表达与ESCC预后不良独立相关，支持mTOR作为ESCC治疗靶点的潜力。
Background. The mammalian target of rapamycin (mTOR) plays central roles in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy level, oxygen level, and mitogenic signals. The aberrant activation of mTOR in relation to clinical outcome has been reported in several types of cancers. mTOR is increasingly important as a potential target for anticancer therapy. Nonetheless, a prognostic feature of mTOR activation in esophageal squamous cell carcinoma (ESCC) remains uncertain.Materials and Methods. First, in order to validate phospho-specific mTOR antibody (Ser2448), phosphorylated mTOR (p-mTOR) expression levels in five ESCC cell lines under cultural conditions with or without everolimus (mTOR inhibitor, also known as RAD001) were evaluated by in vitro immunohistochemistry and immunoblotting. Second, we examined p-mTOR expression by immunohistochemistry using 143 resected ESCC specimens. Prognostic significance of p-mTOR expression was examined by Cox regression and Kaplan-Meier analyses.Results. Among 143 patients, 71(49.7%) were classified into p-mTOR-positive and 72 (50.3%) were classified into p-mTOR-negative. Compared with p-mTOR-negative patients, p-mTOR-positive patients experienced high overall mortality [hazard ratio (HR) 2.44; 95% confidence interval (CI), 1.24-4.83; P = 0.008], which persisted in multivariate analysis (multivariate HR 2.92; 95% CI, 1.48-5.78; P = 0.002). A similar finding was observed for esophageal cancer-specific mortality. p-mTOR expression was not related with any clinical or pathologic variables including age, sex, tumor location, histological grading, operative procedure, T classification (tumor invasion), or lymph-node metastasis.Conclusions. p-mTOR overexpression was independently associated with poor prognosis in ESCC, supporting the potential for mTOR as a therapeutic target for ESCC.