Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer.
Therapeutic evaluation of microRNA-15a and microRNA-16 in ovarian cancer.
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DOI：
10.18632/oncotarget.7618
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发表时间：
2016-03-22
期刊：
影响因子：
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通讯作者：
Bhattacharya R
中科院分区：
文献类型：
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作者：
Dwivedi SK;Mustafi SB;Mangala LS;Jiang D;Pradeep S;Rodriguez-Aguayo C;Ling H;Ivan C;Mukherjee P;Calin GA;Lopez-Berestein G;Sood AK;Bhattacharya R
化疗耐药卵巢癌（OvCa）的治疗仍然具有临床挑战性，迫切需要确定新的治疗策略。在这里，我们报道了促进OvCa进展和化疗耐药的多种机制可以被miR-15a和miR-16的异位表达所抑制。通过对癌症基因组图谱（TCGA）的分析发现，在高级别浆液性（HGS） OvCa患者中，miR-16低表达、BMI1高表达与总生存期（OS）缩短之间存在显著相关性。以BMI1为靶点，在体外用任一microRNA抑制OvCa细胞克隆生长。此外，上皮到间质转化（EMT）和顺铂转运体ATP7B的表达被miR-15a和miR-16抑制，导致细胞外基质降解减少，OvCa细胞对顺铂的敏化增强。在临床前化疗耐药的OvCa原位小鼠模型中，纳米脂质体递送miR-15a和miR-16组合显示，与单用顺铂相比，肿瘤负荷显著降低。因此，随着miR替代疗法的出现，其中一些正在进行2期临床试验，miR-15a和miR-16代表了抗ovca武器库中的新弹药。
Treatment of chemo-resistant ovarian cancer (OvCa) remains clinically challenging and there is a pressing need to identify novel therapeutic strategies. Here we report that multiple mechanisms that promote OvCa progression and chemo-resistance could be inhibited by ectopic expression of miR-15a and miR-16. Significant correlations between low expression of miR-16, high expression of BMI1 and shortened overall survival (OS) were noted in high grade serous (HGS) OvCa patients upon analysis of The Cancer Genome Atlas (TCGA). Targeting BMI1, in vitro with either microRNA reduced clonal growth of OvCa cells. Additionally, epithelial to mesenchymal transition (EMT) as well as expression of the cisplatin transporter ATP7B were inhibited by miR-15a and miR-16 resulting in decreased degradation of the extra-cellular matrix and enhanced sensitization of OvCa cells to cisplatin. Nanoliposomal delivery of the miR-15a and miR-16 combination, in a pre-clinical chemo-resistant orthotopic mouse model of OvCa, demonstrated striking reduction in tumor burden compared to cisplatin alone. Thus, with the advent of miR replacement therapy some of which are in Phase 2 clinical trials, miR-15a and miR-16 represent novel ammunition in the anti-OvCa arsenal.