Li Shau-Hsuan, Chen Chang-Han, Lu Hung-I, Huang Wan-Ting, Tien Wan-Yu, Lan Ya-Chun, Lee Ching-Chang, Chen Yen-Hao, Huang Hsuan-Ying, Chang Alice Y W, Lin Wei-Che
Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Surgery. 2015 Mar;157(3):570-80. doi: 10.1016/j.surg.2014.10.014. Epub 2014 Nov 6.
Although marked improvements have been made in surgical technique and chemoradiotherapy, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) and its downstream signaling, p70 ribosomal S6 protein kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), seem to play central roles in the regulation of cancer cell proliferation and survival. The significance of mTOR and its downstream targets, p70S6K and 4E-BP1, on the prognosis of ESCC remains uncertain, but this pathway is of particular concern because effective inhibitors are already available.
Immunohistochemistry performed to evaluate the expression of phosphorylated mTOR (p-mTOR), phosphorylated p70S6K (p-p70S6K), phosphorylated 4E-binding protein 1 (p-4E-BP1), and Ki-67 using 105 surgically resected ESCC correlated with treatment outcome. The effect of the mTOR signaling pathway inhibitor everolimus on ESCC cell lines were investigated in vitro by the 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and in vivo by a nude mouse xenograft model.
Univariate analysis showed that p-mTOR overexpression (P = .022), p-p70S6K overexpression (P = .002), and Ki-67 labeling index >50% (P = .045) were associated with inferior overall survival (OS). In a multivariate comparison, p-p70S6K overexpression (P = .001; hazard ratio, 2.247) remained independently associated with worse OS. In cell lines and the xenograft model, everolimus significantly inhibited ESCC growth.
Overexpression of p-p70S6K is associated independently with a poor prognosis among patients with ESCC. The mTOR signaling pathway inhibitor everolimus can inhibit ESCC growth in vitro and in vivo. Our findings suggest that inhibition of mTOR signaling pathway may be a promising novel target for ESCC.
尽管手术技术和放化疗已取得显著进步，但食管鳞状细胞癌（ESCC）患者的预后仍不尽人意。雷帕霉素哺乳动物靶点（mTOR）及其下游信号传导，即p70核糖体S6蛋白激酶（p70S6K）和真核翻译起始因子4E（eIF4E）结合蛋白1（4E-BP1），似乎在癌细胞增殖和存活的调控中发挥核心作用。mTOR及其下游靶点p70S6K和4E-BP1对ESCC预后的意义尚不确定，但由于已有有效的抑制剂，该信号通路备受关注。
采用免疫组织化学方法，对105例手术切除的ESCC标本进行检测，评估磷酸化mTOR（p-mTOR）、磷酸化p70S6K（p-p70S6K）、磷酸化4E结合蛋白1（p-4E-BP1）和Ki-67的表达，并与治疗结果相关联。通过噻唑蓝比色法在体外研究mTOR信号通路抑制剂依维莫司对ESCC细胞系的作用，并通过裸鼠异种移植模型在体内进行研究。
单因素分析显示，p-mTOR过表达（P = 0.022）、p-p70S6K过表达（P = 0.002）和Ki-67标记指数>50%（P = 0.045）与总生存期（OS）较差相关。在多因素比较中，p-p70S6K过表达（P = 0.001；风险比，2.247）仍然独立地与较差的OS相关。在细胞系和异种移植模型中，依维莫司显著抑制ESCC生长。
p-p70S6K过表达与ESCC患者的不良预后独立相关。mTOR信号通路抑制剂依维莫司可在体外和体内抑制ESCC生长。我们的研究结果表明，抑制mTOR信号通路可能是ESCC一个有前景的新靶点。
