MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol.
MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol.
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MicroRNA-21 抑制剂使人胶质母细胞瘤细胞 U251（PTEN 突变型）和 LN229（PTEN 野生型）对紫杉醇敏感
DOI：
10.1186/1471-2407-10-27
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发表时间：
2010-01-31
期刊：
影响因子：
3.8
通讯作者：
Kang CS
中科院分区：
文献类型：
--
作者：
Ren Y;Zhou X;Mei M;Yuan XB;Han L;Wang GX;Jia ZF;Xu P;Pu PY;Kang CS
大量数据表明，致癌基因microRNA 21 （miR-21）在多型胶质母细胞瘤（GBM）中显著升高，并调节与癌细胞增殖、凋亡和侵袭性相关的多种基因。因此，miR-21理论上可以成为肿瘤治疗中提高化疗效果的靶点。到目前为止，在人GBM中尚未研究下调miR-21增强紫杉醇化疗效果的作用。方法用紫杉醇和miR-21抑制剂（聚氨基胺（PAMAM）树突状物）单独或联合治疗人类胶质母细胞瘤U251 （PTEN突变体）和LN229 （PTEN野生型）细胞。MTT法测定50%抑菌浓度和细胞活力。采用金正君法分析miR-21抑制剂与抗癌药物紫杉醇之间的作用机制。Annexin V/PI染色，流式细胞术检测细胞凋亡和细胞周期。RT-PCR检测miR-21的表达，western blotting检测恶性肿瘤相关蛋白的改变。结果miR-21抑制剂联合紫杉醇组细胞sic（50）值明显降低，且降幅大于单独紫杉醇组。此外，miR-21抑制剂显著增强了U251细胞和LN229细胞的凋亡，细胞侵袭性明显减弱。有趣的是，上述数据表明，在PTEN突变体和野生型GBM细胞中，miR-21阻断增加了对紫杉醇的化学敏感性。值得注意的是，miR-21抑制剂在u251细胞上与紫杉醇加性相互作用，在LN229细胞上协同作用。因此，miR-21抑制剂可能会中断EGFR通路的活性，而与PTEN状态无关。同时，经miR-21抑制剂和紫杉醇处理后，STAT3和p-STAT3的表达降至较低水平。这些数据有力地表明，miR-21和STAT3之间的调控环可能为了解调节EGFR/STAT3信号传导的机制提供了线索。综上所述，miR-21抑制剂可增强人胶质母细胞瘤细胞对紫杉醇的化学敏感性。miR-21抑制剂和紫杉醇联合使用可能是通过抑制STAT3的表达和磷酸化来控制GBM生长的有效治疗策略。
BackgroundSubstantial data indicate that the oncogene microRNA 21 (miR-21) is significantly elevated in glioblastoma multiforme (GBM) and regulates multiple genes associated with cancer cell proliferation, apoptosis, and invasiveness. Thus, miR-21 can theoretically become a target to enhance the chemotherapeutic effect in cancer therapy. So far, the effect of downregulating miR-21 to enhance the chemotherapeutic effect to taxol has not been studied in human GBM.MethodsHuman glioblastoma U251 (PTEN-mutant) and LN229 (PTEN wild-type) cells were treated with taxol and the miR-21 inhibitor (in a poly (amidoamine) (PAMAM) dendrimer), alone or in combination. The 50% inhibitory concentration and cell viability were determined by the MTT assay. The mechanism between the miR-21 inhibitor and the anticancer drug taxol was analyzed using the Zheng-Jun Jin method. Annexin V/PI staining was performed, and apoptosis and the cell cycle were evaluated by flow cytometry analysis. Expression of miR-21 was investigated by RT-PCR, and western blotting was performed to evaluate malignancy related protein alteration.ResultsIC(50) values were dramatically decreased in cells treated with miR-21 inhibitor combine with taxol, to a greater extent than those treated with taxol alone. Furthermore, the miR-21 inhibitor significantly enhanced apoptosis in both U251 cells and LN229 cells, and cell invasiveness was obviously weakened. Interestingly, the above data suggested that in both the PTEN mutant and the wild-type GBM cells, miR-21 blockage increased the chemosensitivity to taxol. It is worth noting that the miR-21 inhibitor additively interacted with taxol on U251cells and synergistically on LN229 cells. Thus, the miR-21 inhibitor might interrupt the activity of EGFR pathways, independently of PTEN status. Meanwhile, the expression of STAT3 and p-STAT3 decreased to relatively low levels after miR-21 inhibitor and taxol treatment. The data strongly suggested that a regulatory loop between miR-21 and STAT3 might provide an insight into the mechanism of modulating EGFR/STAT3 signaling.ConclusionsTaken together, the miR-21 inhibitor could enhance the chemo-sensitivity of human glioblastoma cells to taxol. A combination of miR-21 inhibitor and taxol could be an effective therapeutic strategy for controlling the growth of GBM by inhibiting STAT3 expression and phosphorylation.
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