Selection of a novel drug-response predictor in esophageal cancer: a novel screening method using microarray and identification of IFITM1 as a potent marker gene of CDDP response.
Selection of a novel drug-response predictor in esophageal cancer: a novel screening method using microarray and identification of IFITM1 as a potent marker gene of CDDP response.
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DOI：
10.3892/ijo.32.2.413
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发表时间：
2008-02
影响因子：
5.2
通讯作者：
S. Fumoto;Tatsushi Shimokuni;K. Tanimoto;K. Hiyama;K. Otani;M. Ohtaki;J. Hihara;Kazuhiro Yoshida
中科院分区：
文献类型：
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作者：
S. Fumoto;Tatsushi Shimokuni;K. Tanimoto;K. Hiyama;K. Otani;M. Ohtaki;J. Hihara;Kazuhiro Yoshida
由于化疗的治疗指数非常狭窄，因此先前实验室对个体药物反应的预测在食管鳞状细胞癌（ESCC）中至关重要。然而，迄今为止，很少有关键标志物被证实用于ESCC。我们以前证明，同时进行两种不同类型的综合基因表达分析可能提供一种方法来确定有效的标记基因的药物敏感性，从表达敏感性相关性分析单独，但筛选方法似乎并不总是有效的。因此，我们试图确定新的有效的标记基因，使用一种新的统计分析的寡核苷酸微阵列表达数据的基础上，一个二维的混合正态模型，并选择了3和7个新的候选5-氟尿嘧啶（5-FU）和顺铂（CDDP），分别。干扰素诱导的跨膜蛋白1（IFITM 1）基因是Wnt信号通路的关键基因，两种筛选方法均选择IFITM 1基因。转染分析和siRNA介导的敲除实验表明，IFITM 1的表达与细胞对顺铂的敏感性密切相关。考虑到药物敏感性是由多个基因决定的事实，我们使用包括IFITM 1在内的一组所有选定标记基因的定量表达数据建立了最佳线性模型，该模型将ESCC细胞系的定量表达数据转换为每种药物的IC 50值。同样，利用体外筛选的代表性基因，我们建立了CDDP/5-FU联合治疗食管癌患者术后无病生存率（DFS）的高度预测公式（R=0.917）。二维混合正态模型是一个强有力的工具，以确定新的药物反应的决定因素，IFITM 1基因的统计方法选择的一个新的关键生物标志物的CDDP在ESCC的反应。
Prior laboratory prediction of individual drug response is of key importance in esophageal squamous cell carcinoma (ESCC), because of the extremely narrow therapeutic index of chemotherapy. However, very few critical markers have been validated to date for ESCC. We previously demonstrated that simultaneous performance of two different types of comprehensive gene expression analysis might provide a way to identify potent marker genes for drug sensitivity from the expression-sensitivity correlation analysis alone, but the screening method appeared not to be always effective. Therefore, we attempted to identify novel potent marker genes using a new statistical analysis of oligonucleotide microarray expression data, based on a two-dimensional mixed normal model, and selected 3 and 7 novel candidates for 5-fluorouracil (5-FU) and cis-platinum (CDDP), respectively. Interferon induced transmembrane protein 1 (IFITM1) gene alone, being suggested as a key gene of Wnt pathway, was commonly selected in both screening methods. The transfection analyses and siRNA-mediated knock-down experiments revealed that expression of IFITM1 closely related to cellular sensitivity to CDDP. Considering the fact that drug sensitivity is determined by multiple genes, we established the best linear model using quantified expression data of a set of all the selected marker genes including IFITM1, which converted the quantified expression data of ESCC cell lines into an IC50 value of each drug. In the same way, using the representative genes selected in vitro, we developed highly predictive formulae for disease-free survival (DFS) of the CDDP/5-FU combination after curative operation in esophageal cancer patients (R=0.917). A two-dimensional mixed normal model can be a powerful tool to identify novel drug-response determinants, and the IFITM1 gene selected by the statistical method a novel critical biomarker of CDDP response in ESCC.