MiRNA-621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity.
MiRNA-621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity.
复制标题
MiRNA-621通过抑制FBXO11和增强p53活性使乳腺癌对化疗敏感
作者：
Xue J;Chi Y;Chen Y;Huang S;Ye X;Niu J;Wang W;Pfeffer LM;Shao ZM;Wu ZH;Wu J
MicroRNA（miRNAs）在调节肿瘤细胞增殖、存活和化疗敏感性方面具有重要作用。使用miRNA预测对癌症治疗的治疗反应的潜在应用具有很高的前景，但具有预测价值的miRNA仍有待鉴定，并且其潜在机制尚未完全理解。在这里，我们显示了miR-621表达与紫杉醇加卡铂（PTX/CBP）方案（乳腺癌患者有效的新辅助化疗）的化疗敏感性之间的强相关性。高水平的miR-621预测乳腺癌患者对PTX/CBP方案新辅助化疗的反应更好，这些患者也倾向于实现病理完全缓解。在培养的乳腺癌细胞和异种移植肿瘤模型中，miR-621的异位过表达促进了细胞凋亡并增加了对PTX和CBP的化疗敏感性。我们进一步表明，FBXO 11是miR-621的直接功能靶点，并且miR-621水平与乳腺癌患者中FBXO 11的表达呈负相关。在PTX或CBP处理后，FBXO 11的异位表达减弱了过表达miR-621的乳腺癌细胞的凋亡增加。因此，FBXO 11高表达与乳腺癌患者的生存率显著相关。从机制上讲，我们在乳腺癌细胞中发现FBXO 11与p53相互作用并促进其neddylation，从而抑制p53的反式活性。因此，miR-621依赖性FBXO 11抑制增强了p53活性，并增加了暴露于化疗药物的乳腺癌细胞的凋亡。综上所述，我们的数据表明，miR-621通过抑制FBXO 11依赖的p53抑制作用，增强乳腺癌细胞对PTX/CBP化疗的化疗敏感性。miR-621可作为乳腺癌治疗的预测性生物标志物和潜在的治疗靶点。
MicroRNAs (miRNAs) have been demonstrated to have critical roles in regulating cancer cell proliferation, survival and sensitivity to chemotherapy. The potential application of using miRNAs to predict therapeutic response to cancer treatment holds high promise, but miRNAs with predictive value remain to be identified and underlying mechanisms have not been completely understood. Here, we show a strong correlation between miR-621 expression and chemosensitivity to paclitaxel plus carboplatin (PTX/CBP) regimen, an effective neoadjuvant chemotherapy for breast cancer patients. High level of miR-621 predicts better response to PTX/CBP regimen neoadjuvant chemotherapy in breast cancer patients, who also tend to achieve pathological complete response. Ectopic overexpression of miR-621 promoted apoptosis and increased chemosensitivity to PTX and CBP both in cultured breast cancer cells and in xenograft tumor model. We further show that FBXO11 is a direct functional target of miR-621 and miR-621 level is negatively correlated with FBXO11 expression in breast cancer patients. Ectopic expression of FBXO11 attenuated increased apoptosis in breast cancer cells overexpressing miR-621 upon PTX or CBP treatment. Consistently, high FBXO11 expression significantly correlated with poor survival in breast cancer patients. Mechanistically, we found in breast cancer cells FBXO11 interacts with p53 and promotes its neddylation, which suppressed the p53 transactivity. Accordingly, miR-621-dependent FBXO11 suppression enhanced p53 activity and increased apoptosis in breast cancer cells exposed to chemotherapeutics. Taken together, our data suggest that miR-621 enhances chemosensitivity of breast cancer cells to PTX/CBP chemotherapy by suppressing FBXO11-depedent inhibition of p53. miR-621 may serve as a predictive biomarker and a potential therapeutic target in breast cancer treatment.