The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells.
The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells.
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DOI：
10.1016/j.molonc.2015.04.015
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发表时间：
2015-10
影响因子：
6.6
通讯作者：
Sikic BI
中科院分区：
文献类型：
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作者：
Brozovic A;Duran GE;Wang YC;Francisco EB;Sikic BI
我们利用卵巢癌细胞株OVCAR-3和MES-OV及其紫杉醇耐药变异体OVCAR-3/TP和MES-OV/TP，研究了miRNA-200家族成员在细胞对紫杉醇和卡铂敏感性中的作用。两种耐药变异体都表现出强烈的上皮-间充质转化(EMT)表型，在OVCAR-3/TP中miR-200C和miR-141的表达显著降低，而在MES-OV/TP中miR-200家族的所有5个成员都下调。慢病毒将miR-200C或miR-141抑制剂导入亲本OVCAR-3细胞，可触发EMT，并使细胞对紫杉醇和卡铂耐药。相反，携带miR-200ab429和200c141簇的逆转录病毒颗粒感染OVCAR-3/TP细胞后，引发了部分间充质向上皮的转变(MET)。这种部分MET不足以使OVCAR-3/TP细胞对紫杉醇重新增敏。然而，miR-200C/miR-141簇转染体对卡铂产生了6-8倍的耐药性，这是一个意想不到的结果，而miR-200a/miR-200b/miR-429则没有影响。用特定的miRNA模拟物感染OVCAR-3/TP GFP细胞证实了这些数据。MIR-200C和miR-141模拟MES-OV/TP细胞对卡铂的耐药性，与OVCAR-3/TP相似，但对紫杉醇增敏。与对照组相比，OVCAR-3/TP 200c141细胞中涉及平衡氧化应激的几个基因发生了改变。在OVCAR-3和MES-OV细胞中，miR-200家族在调节EMT以及对卡铂和紫杉醇的敏感性方面发挥着重要的、细胞上下文相关的作用。对紫杉醇耐药的卵巢癌细胞表现为EMT，并在miRNA-200s中减少。抑制miRNA-200C和141会产生对紫杉醇和卡铂的耐药性。重新引入miRNA-200s可逆转EMT，并使MES-OV/TP对紫杉醇重新敏感。MiRNA-200家族对卡铂耐药有不同的影响。
We studied the role of miRNA‐200 family members in cellular sensitivity to paclitaxel and carboplatin, using two ovarian cancer cell lines, OVCAR‐3 and MES‐OV, and their paclitaxel resistant variants OVCAR‐3/TP and MES‐OV/TP. Both resistant variants display a strong epithelial‐mesenchymal transition (EMT) phenotype, with marked decreases in expression of miR‐200c and miR‐141 in OVCAR‐3/TP, and down‐regulation of all five members of the miR‐200 family in MES‐OV/TP. Lentiviral transfection of inhibitors of miR‐200c or miR‐141 in parental OVCAR‐3 triggered EMT and rendered the cells resistant to paclitaxel and carboplatin. Conversely, the infection of OVCAR‐3/TP cells with retroviral particles carrying the miR‐200ab429 and 200c141 clusters triggered a partial mesenchymal to epithelial transition (MET). This partial MET was not sufficient to re‐sensitize OVCAR‐3/TP cells to paclitaxel. However, the miR‐200c/miR‐141 cluster transfectants became 6–8x resistant to carboplatin, an unexpected result, whereas miR‐200a/miR‐200b/miR‐429 had no effect. Transfecting the OVCAR‐3/TP GFP cells with specific miRNA mimics confirmed these data. MiR‐200c and miR‐141 mimics conferred resistance to carboplatin in MES‐OV/TP cells, similar to OVCAR‐3/TP, but sensitized MES‐OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR‐3/TP 200c141 cells compared to controls. The miR‐200 family plays major, cell‐context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR‐3 and MES‐OV cells. Paclitaxel resistant ovarian cancer cells manifest EMT and decreases in miRNA‐200s. Inhibition of miRNA‐200c and 141 produces resistance to paclitaxel and carboplatin. Re‐introducing miRNA‐200s reverts EMT and re‐sensitizes MES‐OV/TP to paclitaxel. miRNA‐200 family have differential effects on carboplatin resistance.