人肺腺癌多西他赛耐药机制的研究

深入研究肺腺癌对多西他赛(docetaxel,DTX)耐药的分子机制,不仅有助于筛选出可用于临床指导DTX个体化用药的分子靶标,也可为耐药的干预策略研究提供研究方向.笔者课题组采用体外逐步提高DTX浓度的方法诱导建立了稳定传代的人肺腺癌SPC-A1耐DTX细胞系SPC-A1/DTX,并从细胞形态、化疗敏感性、增殖、凋亡、细胞周期、药物转运等方面比较了亲本细胞与耐药细胞间的差异.进一步通过基因芯片及miRNA芯片分析,筛选出耐药细胞中差异表达显著的基因(如ING4)以及miRNA(如miR-200b、miR-100),在体内、外模型中进行功能获得性和(或)缺失性研究,证实ING4表达下调、miR-200b/E2F3及miR-100/Plk-1通路的异常参与了肺腺癌细胞DTX耐药表型的形成.

Research on the mechanisms of docetaxel-resistant human lung adenocarcinoma

In-depth study of the molecular mechanisms of lung adenocarcinoma resistance to docetaxel(DTX) not only offers us the new promising targets of individualized treatment for lung adenocarcinoma patients,but also provides new insights into clinical intervention strategies.In this study,the docetaxel-resistant human lung adenocarcinoma cell line SPC-A1/DTX was derived from parental SPC-A1 cell line by continuous exposure to increasing concentration of DTX in vitro.Differences in biological characteristics,such as cell morphology,chemosensitivity,cell proliferation,apoptosis,cell cycle,and drug transportation were compared between SPC-A1 and SPC-A1/DTX cell lines.Based on gene expression-and miRNA-microarray analysis,differentially expressed genes,such as ING4 and miRNAs(e.g.miR-200b and miR-100) were screened out from SPC-A1/DTX cells.With further gain-of-function and(or) loss-of-function studies of these molecules in both in vitro and in vivo models,we provided potential mechanistic explanations for DTX resistance of human lung adenocarcinoma.It was found that down-regulation of ING4 gene and abnormalities of crosstalk between miR-200b and E2F3 gene and crosstalk between miR-100 and Plk-1 gene might be essential for DTX resistance in human lung adenocarcinoma.