Identification of Docetaxel Resistance Genes in Castration-Resistant Prostate Cancer
Identification of Docetaxel Resistance Genes in Castration-Resistant Prostate Cancer
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DOI：
10.1158/1535-7163.mct-11-0289
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发表时间：
2012-02-01
影响因子：
5.7
通讯作者：
Mellado, Begona
中科院分区：
文献类型：
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作者：
Marin-Aguilera, Mercedes;Codony-Servat, Jordi;Mellado, Begona
基于多西紫杉醇的化疗是转移性去势抵抗性前列腺癌（CRPC）的标准一线治疗。然而，大多数患者最终会对这种治疗产生耐药性。在这项研究中，我们的目的是在两种多西他赛耐药性 CRPC 细胞系模型中鉴定与多西他赛耐药性相关的关键分子基因和网络，并测试来自 CRPC 患者的肿瘤样本中差异最大的表达基因。 DU-145和PC-3细胞分别转化为多西紫杉醇抗性细胞DU-145R和PC-3R。全基因组阵列用于比较这四种细胞系之间的全局基因表达。结果显示 DU-145R 和 PC-3R 细胞共有 243 个基因存在差异表达（P < 0.05，Bonferroni 调整的 P 值和对数比 > 1.2）。这些基因参与细胞生长、发育、死亡、增殖、运动和基因表达等过程。通过 Ingenuity Pathways Analysis 研究了 DU-145R 和 PC-3R 细胞中普遍失调的基因和网络。在多西紫杉醇存在的情况下，将亲本细胞暴露于 TGFB1 可以增加它们的存活率，这表明 TGF-β 超家族在赋予耐药性方面发挥着作用。通过实时定量逆转录酶 PCR 在所有四种细胞系中验证了 18 个选定基因的表达变化，并在一组 11 个 FFPE 和 5 个最佳切割温度肿瘤样本中进行了测试。对患者的分析显示，在多西他赛耐药肿瘤中，CDH1 和 IFIH1 等表达显着下调。该探索性分析提供了有关 CRPC 多西紫杉醇耐药性的潜在基因和网络参与的信息。需要对这些结果进行进一步的临床验证，以开发针对 CRPC 患者的靶向疗法，以规避这种治疗耐药性。摩尔癌症治疗； 11(2)；329-39。 (C) 2011 年 AACR。
Docetaxel-based chemotherapy is the standard first-line therapy in metastatic castration-resistant prostate cancer (CRPC). However, most patients eventually develop resistance to this treatment. In this study, we aimed to identify key molecular genes and networks associated with docetaxel resistance in two models of docetaxel-resistant CRPC cell lines and to test for the most differentially expressed genes in tumor samples from patients with CRPC. DU-145 and PC-3 cells were converted to docetaxel-resistant cells, DU-145R and PC-3R, respectively. Whole-genome arrays were used to compare global gene expression between these four cell lines. Results showed differential expression of 243 genes (P < 0.05, Bonferroni-adjusted P values and log ratio > 1.2) that were common to DU-145R and PC-3R cells. These genes were involved in cell processes like growth, development, death, proliferation, movement, and gene expression. Genes and networks commonly deregulated in both DU-145R and PC-3R cells were studied by Ingenuity Pathways Analysis. Exposing parental cells to TGFB1 increased their survival in the presence of docetaxel, suggesting a role of the TGF-beta superfamily in conferring drug resistance. Changes in expression of 18 selected genes were validated by real-time quantitative reverse transcriptase PCR in all four cell lines and tested in a set of 11 FFPE and five optimal cutting temperature tumor samples. Analysis in patients showed a noteworthy downexpression of CDH1 and IFIH1, among others, in docetaxel-resistant tumors. This exploratory analysis provides information about potential gene and network involvement in docetaxel resistance in CRPC. Further clinical validation of these results is needed to develop targeted therapies in patients with CRPC that can circumvent such resistance to treatment. Mol Cancer Ther; 11(2);329-39. (C) 2011 AACR.