Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells.
Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells.
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DOI：
10.18632/oncotarget.8966
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Sharma M
中科院分区：
文献类型：
--
作者：
De A;Powers B;De A;Zhou J;Sharma S;Van Veldhuizen P;Bansal A;Sharma R;Sharma M
卵巢癌(OC)对目前基于手术、化疗和放射治疗相结合的治疗策略具有高度的抵抗力。我们最近在体外和体内实验中证实了丁香醇提物对OC细胞的抗肿瘤作用。我们假设AE通过microRNA(MiR)调控机制抑制OC的生长(S)。AE对SKOV3细胞的增殖、迁移和侵袭力的抑制作用(P≤0.001)，以及在异种移植小鼠模型中肿瘤生长的90%抑制作用表明有多个靶点。对与OC相关的microRNA的RT-qPCR分析显示，经AE处理的SKOV3细胞中miR-375的表达增加了2,000倍，而外源性miR-375抑制剂可阻断该表达(P≤0.001)。AE还降低了miR-375靶基因IGF1R(P≤0.001)和抑制E-钙粘蛋白表达的EMT相关转录因子SNAIL 1(P≤0.002)的基因和蛋白表达(P≤0.003)。AE使E-钙粘附素表达增加(P≤0.001)。经AE处理的SKOV3细胞培养上清液中外切体miR375表达增加(P≤.0.0 1)。最后，在SKOV3来源的异种移植瘤减毒过程中，AE显著降低IGF1R和SNAIL1蛋白的表达。综上所述，这些结果表明，AE通过激活miR-375和通过靶向OC细胞中的IGF1R和SNAIL1来调节癌细胞和肿瘤微环境。
Ovarian cancer (OC) is highly resistant to current treatment strategies based on a combination of surgery, chemotherapy and radiation therapy. We have recently demonstrated the anti-neoplastic effect of Amla extract (Emblica officinalis, AE) on OC cells in vitro and in vivo. We hypothesized that AE attenuates growth of OC through microRNA (miR)-regulated mechanism(s). The inhibitory effect of AE on proliferation, migration and invasiveness (P≤0.001) of SKOV3 cells and >90% attenuation of tumor growth in a xenograft mouse model suggested multiple targets. RT-qPCR analysis of microRNAs associated with OC showed a >2,000-fold increase in the expression of miR-375 in AE-treated SKOV3 cells that was blocked by an exogenous miR-375 inhibitor (P≤0.001). AE also decreased the gene and protein expression of IGF1R, a target of miR-375 (P≤0.001), and SNAIL1 (P≤0.002), an EMT-associated transcription factor that represses E-cadherin expression (P≤0.003). AE increased E-cadherin expression (P≤0.001). Treatment of SKOV3 cells with AE resulted in increased miR-375 in exosomes in the medium (P≤0.01). Finally, AE significantly decreased the expression of IGF1R and SNAIL1 proteins during attenuation of SKOV3-derived xenograft tumor. Together, these results show that AE modulates cancer cells and the tumor microenvironment via activation of miR-375 and by targeting IGF1R and SNAIL1 in OC cells.
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影响因子：
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