Survivin-targeting miR-542-3p overcomes HER3 signaling-induced chemoresistance and enhances the antitumor activity of paclitaxel against HER2-overexpressing breast cancer.
Survivin-targeting miR-542-3p overcomes HER3 signaling-induced chemoresistance and enhances the antitumor activity of paclitaxel against HER2-overexpressing breast cancer.
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DOI：
10.1016/j.canlet.2018.01.065
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发表时间：
2018-04-28
期刊：
影响因子：
9.7
通讯作者：
Liu B
中科院分区：
文献类型：
--
作者：
Lyu H;Wang S;Huang J;Wang B;He Z;Liu B
HER3 的表达升高与乳腺癌细胞中的 HER2 相互作用，通过磷酸肌醇 3-激酶 (PI-3K)/Akt 依赖性的 Survivin 上调赋予化疗耐药性。然而，其根本机制尚不清楚。在 HER2 过度表达的乳腺癌细胞中，HER3 的异位表达或特异性敲除不会改变 Survivin mRNA 水平和 Survivin 蛋白稳定性，这支持了 HER3 信号传导可能调节靶向 Survivin 的特定 miRNA 以改变其蛋白翻译的观点。在这里，我们发现 HER3 的过表达和特异性敲低分别降低和增强了乳腺癌细胞中两种靶向生存素的 miRNA miR-203 和 miR-542-3p 的表达。虽然 miR-203 或 miR-542-3p 的特异性抑制剂减弱了抗 HER3 抗体诱导的生存素下调，但抑制 miR-542-3p 表现出比抑制 miR-203 更好的功效。一致的是，miR-542-3p 模拟物比 miR-203 模拟物不仅在抑制生存素方面更有效，而且在增强 HER2 过表达乳腺癌细胞中紫杉醇诱导的细胞凋亡方面也更有效。此外，与单独使用任一药物相比，miR-542-3p模拟物和紫杉醇的组合可显着抑制HER2过表达乳腺癌细胞的体内肿瘤生长。总的来说，我们的数据表明 HER3/PI-3K/Akt 信号传导通过抑制 miR-203 和 miR-542-3p 上调 Survivin。由于 miR-542-3p 在 Survivin mRNA 的 3'-UTR 上具有三个结合位点，因此其模拟物能够在体外和体内有效下调 Survivin。因此，miR-542-3p替代疗法是克服HER3介导的紫杉醇耐药性的极好方法，并显着增强紫杉醇对HER2过表达乳腺癌的抗肿瘤活性。
Elevated expression of HER3, which interacts with HER2 in breast cancer cells, confers chemoresistance via phosphoinositide 3-kinase (PI-3K)/Akt-dependent upregulation of Survivin. However, the underlying mechanism is not clear. Ectopic expression or specific knockdown of HER3 in HER2-overexpressing breast cancer cells did not alter Survivin mRNA levels and Survivin protein stability, supporting the notion that HER3 signaling may regulate specific miRNAs that target Survivin to alter its protein translation. Here we showed that overexpression and specific knockdown of HER3 reduced and enhanced expression of two Survivin-targeting miRNAs, miR-203 and miR-542-3p, in breast cancer cells, respectively. While the specific inhibitor of either miR-203 or miR-542-3p attenuated an anti-HER3 antibody-induced downregulation of Survivin, inhibition of miR-542-3p exhibited a better efficacy than miR-203 inhibition did. Consistently, miR-542-3p mimic was much more effective than miR-203 mimic not only in inhibition of Survivin, but also in enhancement of paclitaxel-induced apoptosis in HER2-overexpressing breast cancer cells. Moreover, the combination of miR-542-3p mimic and paclitaxel, as compared with either agent alone, significantly inhibited in vivo tumor growth of HER2-overexpressing breast cancer cells. Collectively, our data indicated that the HER3/PI-3K/Akt signaling upregulates Survivin via suppression of miR-203 and miR-542-3p. Because miR-542-3p has three binding sites on the 3′-UTR of Survivin mRNA, its mimic was able to effectively downregulate Survivin in vitro and in vivo. Thus, miR-542-3p-replacement therapy is an excellent approach to overcome HER3-mediated paclitaxel resistance and significantly enhances the antitumor activity of paclitaxel against HER2-overexpressing breast cancer.
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作者：
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抗 erbB3 抗体 MM-121/SAR256212 与曲妥珠单抗联合使用，可对曲妥珠单抗耐药的乳腺癌细胞发挥有效的抗肿瘤活性。
影响因子：
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