Plasma membrane proteomics identifies bone marrow stromal antigen 2 as a potential therapeutic target in endometrial cancer
Plasma membrane proteomics identifies bone marrow stromal antigen 2 as a potential therapeutic target in endometrial cancer
复制标题
DOI：
10.1002/ijc.27679
复制
发表时间：
2013-01-15
影响因子：
6.4
通讯作者：
Naka, Tetsuji
中科院分区：
文献类型：
--
作者：
Yokoyama, Takuhei;Enomoto, Takayuki;Naka, Tetsuji
本报告利用一种新的蛋白质组学方法发现子宫内膜癌的潜在治疗靶点。我们使用了一种基于生物素化的细胞表面蛋白富集的方法，结合同量异位素标签的相对和绝对定量（iTRAQ）技术，使用纳米液相色谱串联质谱分析，以确定子宫内膜癌细胞与正常子宫内膜细胞相比，特异性过表达的蛋白质。我们共鉴定了272种蛋白质，其中包括11种质膜蛋白，与正常子宫内膜细胞系相比，在7种子宫内膜癌细胞系中至少有4种细胞系中，其表达增加了2倍以上。检测到骨髓基质抗原2（BST 2）的过表达，并通过使用临床样本的免疫组化分析支持观察结果。118例子宫内膜癌组织中BST2的表达较59例正常子宫内膜组织中BST2的表达更具有特征性（p < 0.0001）。在体外和体内研究抗BST 2抗体的治疗效果。抗BST 2单克隆抗体通过抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性在BST 2阳性子宫内膜癌细胞中显示出体外细胞毒性。在体内异种移植模型中，抗BST 2抗体治疗以NK细胞依赖性方式显著抑制BST 2阳性子宫内膜癌细胞的肿瘤生长。抗BST 2抗体在体外和体内均对子宫内膜癌具有有效的抗肿瘤作用，表明抗BST 2抗体用于子宫内膜癌治疗的临床应用的强大潜力。基于生物素化的细胞表面蛋白富集和iTRAQ分析的组合应该是未来发现潜在治疗靶点的有用筛选方法。
This report utilizes a novel proteomic method for discovering potential therapeutic targets in endometrial cancer. We used a biotinylation-based approach for cell-surface protein enrichment combined with isobaric tags for relative and absolute quantitation (iTRAQ) technology using nano liquid chromatographytandem mass spectrometry analysis to identify specifically overexpressed proteins in endometrial cancer cells compared with normal endometrial cells. We identified a total of 272 proteins, including 11 plasma membrane proteins, whose expression increased more than twofold in at least four of seven endometrial cancer cell lines compared with a normal endometrial cell line. Overexpression of bone marrow stromal antigen 2 (BST2) was detected and the observation was supported by immunohistochemical analysis using clinical samples. The expression of BST2 was more characteristic of 118 endometrial cancer tissues compared with 59 normal endometrial tissues (p < 0.0001). The therapeutic effect of an anti-BST2 antibody was studied both in vitro and in vivo. An anti-BST2 monoclonal antibody showed in vitro cytotoxicity in BST2-positive endometrial cancer cells via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. In an in vivo xenograft model, anti-BST2 antibody treatment significantly inhibited tumor growth of BST2-positive endometrial cancer cells in an NK cell-dependent manner. The anti-BST2 antibody had a potent antitumor effect against endometrial cancer both in vitro and in vivo, indicating a strong potential for clinical use of anti-BST2 antibody for endometrial cancer treatment. The combination of biotinylation-based enrichment of cell-surface proteins and iTRAQ analysis should be a useful screening method for future discovery of potential therapeutic targets.