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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。
In-depth study of the molecular mechanism of lung adenocarcinoma resistance to docetaxel (DTX) not only helps to screen out molecular targets that can be used clinically to guide the individualized use of DTX, but also to provide evidence for the study of drug resistance intervention strategies direction. In this study, we established a stable subcultured human lung adenocarcinoma SPC-A1 DTX cell line SPC-A1 / DTX by gradually increasing the concentration of DTX in vitro and from the aspects of cell morphology, chemosensitivity, proliferation, apoptosis, cell cycle , Drug transport and other aspects compared the difference between the parental cells and drug-resistant cells. Further analysis of gene chips and miRNA microarray revealed that genes (such as ING4) and miRNAs (such as miR-200b and miR-100) that were significantly differentially expressed in drug resistant cells were screened for functional availability and ) Deletion studies confirmed that ING4 expression was downregulated. The abnormalities of miR-200b / E2F3 and miR-100 / Plk-1 pathway were involved in the formation of DTX resistant phenotype in lung adenocarcinoma cells.