Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer
Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer
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DOI：
10.1007/s00280-017-3238-4
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发表时间：
2017-02
影响因子：
3
通讯作者：
Jing Zhang;Jinyu Liu;Xin-Yan Xu;Li Li-Li
中科院分区：
文献类型：
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作者：
Jing Zhang;Jinyu Liu;Xin-Yan Xu;Li Li-Li
目的探讨姜黄素对卵巢癌细胞外小泡(EVS)转运耐药能力的影响。方法收集顺铂耐药的A2780cp细胞经姜黄素处理(EVS-CU)和未处理(EVS-N)后的EVS，进行IncRNA图谱分析。MSP法检测姜黄素对MEG3启动子甲基化的影响；定量RT-PCR法检测姜黄素对MEG3基因表达的影响。进一步研究MEG3对miR-214表达的调节作用以及EVS介导的miR-214转导在顺铂耐药中的作用。结果姜黄素减弱了EVS-N诱导EVS-N耐药的能力，并诱导EVS中lncRNAs发生明显变化。MEG3是一种表达上调最强的lncRNAs。姜黄素导致MEG3启动子区域去甲基化，5-AZA-DC处理使MEG3表达恢复，且呈剂量依赖关系。MEG3与miR-214之间至少有两个结合位点。姜黄素对MEG3的修复作用显著降低了细胞和EVS中的miR-214。在功能上，miR-214抑制减弱了EVS-N增强化疗耐药性的能力，而miR-214过表达则增强了EVS-CU诱导化疗耐药的能力。结论姜黄素可通过去甲基化恢复MEG3水平。MEG3上调可减少EVS介导的miR-214在卵巢癌细胞中的转移，从而降低耐药性。
PurposeTo investigate how curcumin alters the extracellular vesicles’ (EVs) capability to ship drug resistance in ovarian cancer.MethodsThe EVs from cisplatin-resistant A2780cp cells with curcumin treatment (EVs-CU) or without curcumin treatment (EVs-N) were collected for lncRNA profiling. Curcumin’s effect on MEG3 promoter methylation and MEG3 expression were studied by MSP and qRT-PCR, respectively. The regulative effect of MEG3 on miR-214 expression and the functional role of EVs mediated transfer of miR-214 in cisplatin resistance were further investigated.ResultsCurcumin weakened the EVs-N’s capability to induce drug resistance and induced significant changes of lncRNAs in the EVs. MEG3 is one of the most upregulated lncRNAs. Curcumin led to demethylation in the promoter region of MEG3 and 5-AZA-dC treatment restored MEG3 expression in a dose dependent manner. There were at least two binding sites between MEG3 and miR-214. MEG3 restoration by curcumin significantly reduced miR-214 in cells and in EVs. Functionally, miR-214 inhibition weakened the EVs-N’s capability to enhance chemoresistance, while miR-214 overexpression increased the capability of EVs-CU in inducing chemoresistance.ConclusionCurcumin can restore MEG3 levels via demethylation. MEG3 upregulation can decrease EVs mediated transfer of miR-214 in ovarian cancer cells, thereby reducing drug resistance.