Survivin-targeting miR-542-3p overcomes HER3 signaling-induced chemoresistance and enhances the antitumor activity of paclitaxel against HER2-overexpressing breast cancer.
生存素靶向 miR-542-3p 克服 HER3 信号诱导的化疗耐药性,增强紫杉醇对 HER2-overexpressing 乳腺癌的抗肿瘤活性。

摘要

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.

译文

HER3 的表达升高,与 HER2 在乳腺癌细胞中的相互作用,通过磷酸肌醇 3-激酶 (PI-3K)/Akt 依赖的生存素上调给予化疗抵抗。然而,潜在的机制尚不清楚。HER3 在 HER2-overexpressing 乳腺癌细胞中的异位表达或特异性敲除并没有改变生存素 mRNA 水平和生存素蛋白稳定性, 支持 HER3 信号可能调节靶向生存素的特定 miRNAs 以改变其蛋白质翻译的概念。在这里,我们表明 HER3 的过表达和特异性敲除分别减少和增强了乳腺癌细胞中两种针对生存素的 miRNAs,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 anti-HER3 抗体诱导的生存素的下调,但抑制 miR-542-3p 表现出比 miR-203 抑制更好的疗效。一致地,miR-542-3p 模拟物比 miR-203 模拟物更有效,不仅在抑制生存素方面,而且在增强紫杉醇诱导的 HER2-overexpressing 乳腺癌细胞凋亡方面。此外,与单独使用任何一种药物相比,miR-542-3p 模拟物和紫杉醇的组合显著抑制了 HER2-overexpressing 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 信号通过抑制 miR-203 和 miR-542-3p 上调生存素。由于 miR-542-3p 在生存素 mRNA 的 3 '-UTR 上有三个结合位点,其模拟物能够在体内外有效下调生存素。因此,miR-542-3p-replacement 疗法是克服紫杉醇耐药性 HER3-mediated 极好的方法,并显著增强紫杉醇对 HER2-overexpressing 乳腺癌的抗肿瘤活性。

Survivin

肿瘤 基础研究 临床研究术语
概述  :  

生存素是1987年发现的凋亡抑制蛋白(inhibitor of apoptosis proteins,IAP)家族成员。该类蛋白特异性抑制caspase 3、7、9的活性而抑制细胞凋亡。它的表达不受肿瘤坏死因子α/核因子κB信号通路的调控。X-线衍射发现生存素以二聚体结构存在。由于其独特的结构、特殊的组织分布以及功能的多样性,特别是近年来体内外实验发现survivin靶向治疗能够诱导细胞凋亡、明显抑制肿瘤生长,而备受关注。 分子生物学survivin基因定位于染色体17q25区,靠

Survivin

       n. 生存素;存活素

       Conclusion:Survivin is the target gene of JAK-STAT pathway, and played an important role in the cytoprotective effect of H2O2 preconditioning. 结论:生存素是JAK-STAT通路的靶基因,可能在H2O2预处理诱导的适应性细胞保护机制中起着重要的作用。

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