Chemosensitivity profile of cancer cell lines and identification of genes determining chemosensitivity by an integrated bioinformatical approach using cDNA arrays
Chemosensitivity profile of cancer cell lines and identification of genes determining chemosensitivity by an integrated bioinformatical approach using cDNA arrays
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DOI：
10.1158/1535-7163.mct-04-0234
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发表时间：
2005-03
影响因子：
5.7
通讯作者：
N. Nakatsu;Y. Yoshida;K. Yamazaki;Tomoki Nakamura;S. Dan;Y. Fukui;T. Yamori
中科院分区：
文献类型：
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作者：
N. Nakatsu;Y. Yoshida;K. Yamazaki;Tomoki Nakamura;S. Dan;Y. Fukui;T. Yamori
我们建立了一组45个人类癌细胞系（JFCR-45），以探索决定这些细胞系对抗癌药物的化学敏感性的基因。JFCR-45包含源自三种不同器官的肿瘤的癌细胞系：乳腺、肝脏和胃。纳入胃癌和肝癌细胞系是本研究的一个主要新奇点。我们确定了53种抗癌药物在每个细胞系中可诱导50%生长抑制（GI 50）的浓度。使用GI 50的聚类分析表明，JFCR-45可以允许基于其作用模式对药物进行分类，这与NCI-60和JFCR-39中的先前发现一致。我们接下来研究了JFCR-45中的基因表达，并开发了这组细胞系中化学敏感性和基因表达的综合数据库。我们应用基因表达谱和化疗敏感性谱之间的相关性分析，这揭示了许多与癌细胞对抗癌药物的敏感性相关的候选基因。为了鉴定直接决定化疗敏感性的基因，我们进一步测试了这些候选基因在人纤维肉瘤HT 1080中单独过表达每个基因后改变抗癌药物敏感性的能力。我们观察到，HT 1080细胞转染HSPA 1A和JUN基因，实际上提高了丝裂霉素C的敏感性，这表明这些基因直接参与丝裂霉素C的敏感性。这些结果表明，一个综合的生物信息学方法，使用化疗敏感性和基因表达谱是有用的，用于确定基因的癌细胞的化疗敏感性。
We have established a panel of 45 human cancer cell lines (JFCR-45) to explore genes that determine the chemosensitivity of these cell lines to anticancer drugs. JFCR-45 comprises cancer cell lines derived from tumors of three different organs: breast, liver, and stomach. The inclusion of cell lines derived from gastric and hepatic cancers is a major point of novelty of this study. We determined the concentration of 53 anticancer drugs that could induce 50% growth inhibition (GI50) in each cell line. Cluster analysis using the GI50s indicated that JFCR-45 could allow classification of the drugs based on their modes of action, which coincides with previous findings in NCI-60 and JFCR-39. We next investigated gene expression in JFCR-45 and developed an integrated database of chemosensitivity and gene expression in this panel of cell lines. We applied a correlation analysis between gene expression profiles and chemosensitivity profiles, which revealed many candidate genes related to the sensitivity of cancer cells to anticancer drugs. To identify genes that directly determine chemosensitivity, we further tested the ability of these candidate genes to alter sensitivity to anticancer drugs after individually overexpressing each gene in human fibrosarcoma HT1080. We observed that transfection of HT1080 cells with the HSPA1A and JUN genes actually enhanced the sensitivity to mitomycin C, suggesting the direct participation of these genes in mitomycin C sensitivity. These results suggest that an integrated bioinformatical approach using chemosensitivity and gene expression profiling is useful for the identification of genes determining chemosensitivity of cancer cells.