miR-221 silencing blocks hepatocellular carcinoma and promotes survival.
miR-221 silencing blocks hepatocellular carcinoma and promotes survival.
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DOI：
10.1158/0008-5472.can-11-1144
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Schmittgen TD
中科院分区：
文献类型：
--
作者：
Park JK;Kogure T;Nuovo GJ;Jiang J;He L;Kim JH;Phelps MA;Papenfuss TL;Croce CM;Patel T;Schmittgen TD
由于缺乏有效的治疗方法，晚期肝细胞癌（HCC）患者的预后很差。为了解决这种情况，我们进行了一项针对致癌microRNA miR-221的寡核苷酸治疗效果的临床前研究，miR-221与HCC有关。在评估的9种化学物质中，我们确定2′-O-甲基硫代磷酸酯修饰的抗miR-221寡核苷酸在体外降低增殖方面最有效。与未修饰的寡核苷酸相比，胆固醇修饰的抗miR-221亚型（chol-抗miR-221）表现出改善的药代动力学和肝组织分布。Chol-anti-miR-221在静脉内给药一周内显著降低了肝脏中的miR-221水平，原位杂交研究证实了寡核苷酸在体内肿瘤细胞中的蓄积。在同一时期内，chol-抗-miR-221减少了肿瘤细胞增殖，增加了细胞凋亡和细胞周期停滞的标志物，延长了肿瘤倍增时间并提高了小鼠存活率。综上所述，我们的研究结果为chol-抗miR-221在有效的原位肝癌小鼠模型中的疗效提供了临床前证据，表明这种靶向药物可能有利于晚期肝癌患者的治疗。
Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis due to a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221 which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2′-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared to unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment of advanced HCC patients.