Targeting c-MYC in Platinum-Resistant Ovarian Cancer.
Targeting c-MYC in Platinum-Resistant Ovarian Cancer.
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DOI：
10.1158/1535-7163.mct-14-0801
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发表时间：
2015-10
影响因子：
5.7
通讯作者：
Vivas-Mejía PE
中科院分区：
文献类型：
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作者：
Reyes-González JM;Armaiz-Peña GN;Mangala LS;Valiyeva F;Ivan C;Pradeep S;Echevarría-Vargas IM;Rivera-Reyes A;Sood AK;Vivas-Mejía PE
本研究旨在探讨小干扰RNA(SiRNA)介导的c-myc沉默在顺铂耐药卵巢癌中的分子和治疗作用。从癌症基因组图谱(TCGA)门户网站提取的患者数据的统计分析显示，c-MYC mRNA水平高的卵巢癌患者的无进展(PFS)和总体(OS)生存率下降。此外，对一组卵巢癌细胞株的分析表明，与顺铂敏感的细胞相比，顺铂耐药的细胞中c-myc蛋白水平更高。在顺铂耐药的卵巢癌细胞中，也评估了siRNA介导的c-myc沉默后，小鼠异种移植模型的体外细胞活力、生长、细胞周期进展、细胞凋亡以及体内治疗效果。在siRNA介导的c-MYC耗竭后，观察到显著的细胞生长和活力抑制、细胞周期停滞和细胞凋亡的激活。此外，单周剂量的c-myc-siRNA被掺入基于1，2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)-1，2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene-2000(DSPE-PEG2000)的纳米脂质体中，显著减少了肿瘤的生长。这些发现确定c-myc是高水平表达该癌蛋白的卵巢癌的潜在治疗靶点。
The purpose of this study was to investigate the molecular and therapeutic effects of small-interfering RNA (siRNA)-mediated c-MYC silencing in cisplatin-resistant ovarian cancer. Statistical analysis of patient’s data extracted from The Cancer Genome Atlas (TCGA) portal showed that the progression free- (PFS) and the overall (OS) survival were decreased in ovarian cancer patients with high c-MYC mRNA levels. Furthermore, analysis of a panel of ovarian cancer cell lines showed that c-MYC protein levels were higher in cisplatin-resistant cells when compared to their cisplatin-sensitive counterparts. In vitro cell viability, growth, cell cycle progression, and apoptosis, as well as in vivo therapeutic effectiveness in murine xenograft models, were also assessed following siRNA-mediated c-MYC silencing in cisplatin-resistant ovarian cancer cells. Significant inhibition of cell growth and viability, cell cycle arrest, and activation of apoptosis, were observed upon siRNA-mediated c-MYC depletion. In addition, single weekly doses of c-MYC-siRNA incorporated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG-2000)-based nanoliposomes resulted in significant reduction in tumor growth. These findings identify c-MYC as a potential therapeutic target for ovarian cancers expressing high levels of this oncoprotein.