Goto Tomoko, Takano Masashi, Sakamoto Masaru, Kondo Ayako, Hirata Junko, Kita Tsunekazu, Tsuda Hitoshi, Tenjin Yoshio, Kikuchi Yoshihiro
Department of Obstetrics and Gynecology, Saitama Medical College, Iruma-gun, Saitama 350-0495, Japan.
Oncol Rep. 2006 May;15(5):1265-71.
In the current study, we identified paclitaxel-resistant related genes by comparing gene expression profiles of paclitaxel-resistant and parent ovarian cancer cell lines. Gene expression profiles of the human ovarian cancer cell line (KF28), cisplatin-resistant cell line (KFr13) induced from KF28, and paclitaxel-resistant cell lines (KF28TX and KFr13TX) induced by exposing KF28 and KFr13 to dose-escalating paclitaxel were compared and analyzed using cDNA microarray. Of 557 human cancer-related cDNA transcripts compared, 5 genes were found to be underexpressed and 5 genes overexpressed in the paclitaxel-resistant KF28TX, while another paclitaxel-resistant KFr13TX had 5 underexpressed and 8 overexpressed genes. Among these genes, overexpression of the ATP-binding cassette subfamily (MDR-1), Rho guanine dinucleotide phosphate dissociation inhibitor beta (RhoGDI) and insulin-like growth factor binding protein 3 (IGFBP-3) was observed in both paclitaxel-resistant cell lines. Using real-time quantitative PCR, we confirmed the array results. We therefore conclude that IGFBP-3, RhoGDI and MDR-1 were correlated with paclitaxel resistance. Moreover, immunohistochemical staining was analyzed in 22 serous ovarian cancer tissues from patients who received paclitaxel-based chemotherapy, and RhoGDI overexpression was observed more frequently in non-responsers than in responders (p=0.004). RhoGDI expression proved to be a predictive marker of paclitaxel resistance not only in paclitaxel-resistant cell lines, but also in clinical samples.
在本研究中，我们通过比较紫杉醇耐药和亲本卵巢癌细胞系的基因表达谱，鉴定出了与紫杉醇耐药相关的基因。使用cDNA微阵列比较并分析了人卵巢癌细胞系（KF28）、由KF28诱导产生的顺铂耐药细胞系（KFr13）以及通过将KF28和KFr13暴露于剂量递增的紫杉醇而诱导产生的紫杉醇耐药细胞系（KF28TX和KFr13TX）的基因表达谱。在比较的557个人类癌症相关cDNA转录本中，发现5个基因在紫杉醇耐药的KF28TX中表达下调，5个基因表达上调，而另一个紫杉醇耐药的KFr13TX有5个表达下调的基因和8个表达上调的基因。在这些基因中，在两个紫杉醇耐药细胞系中均观察到ATP结合盒亚家族（MDR-1）、Rho鸟嘌呤二磷酸解离抑制剂β（RhoGDI）和胰岛素样生长因子结合蛋白3（IGFBP-3）的过表达。我们使用实时定量PCR证实了阵列结果。因此，我们得出结论，IGFBP-3、RhoGDI和MDR-1与紫杉醇耐药相关。此外，对22例接受以紫杉醇为基础化疗的浆液性卵巢癌患者的组织进行了免疫组化染色分析，结果显示，无反应者中RhoGDI过表达的频率高于反应者（p=0.004）。RhoGDI表达不仅在紫杉醇耐药细胞系中，而且在临床样本中都被证明是紫杉醇耐药的预测标志物。
