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miR-770-5p 参与曲妥珠单抗在 HER2 阳性乳腺癌细胞中的反应。

Involvement of miR-770-5p in trastuzumab response in HER2 positive breast cancer cells.

机构信息

Biotechnology Institute, Ankara University, Ankara, Turkey.

Department of Medical Pharmacology, Faculty of Medicine, Ankara University, Ankara,Turkey.

出版信息

PLoS One. 2019 Apr 22;14(4):e0215894. doi: 10.1371/journal.pone.0215894. eCollection 2019.

Abstract

miRNAs may play effective roles in breast cancer so modulating their expression levels could have therapeutic benefits. Recent studies have found the combination of miRNA-based therapeutics with conventional drugs as promising. This study aimed to find drug-responsive miRNAs, and explore their anticancer activities in HER2+ breast cancer cells and regulatory role in the trastuzumab response. qRT-PCR-array analysis was performed with effective concentrations of tamoxifen and trastuzumab treated BT-474, SK-BR-3 and MCF-7 cells. Motility and invasion analyses were performed with wound healing and xCELLigence impedance-based assays respectively. Viability of cells following mimic transfection and drug treatment was assessed by WST-1 assay. Western blot analysis was used to assess miR-770-5p regulation of proteins and their phosphorylated forms. The clinical relevance of miR-770-5p was examined by TCGA data analysis. The qRT-PCR-array results indicated that miR-770-5p was responsive in a drug and cell line independent manner. Overexpression of miR-770-5p inhibited the motility and cell invasion through regulation of AKT and ERK proteins. Additionally, miR-770-5p potentiated the effectiveness of trastuzumab. Thus, regulating the expression level of miR-770-5p in combination with trastuzumab treatment may simultaneously inhibit the downstream elements of PI3K and MAPK signalling, thereby blocking the proliferation, motility and invasion capacities of HER2+ breast cancer cells.

摘要

miRNAs 可能在乳腺癌中发挥有效作用,因此调节其表达水平可能具有治疗益处。最近的研究发现,将 miRNA 治疗与传统药物联合使用具有很大的潜力。本研究旨在寻找药物反应性 miRNAs,并探索它们在 HER2+乳腺癌细胞中的抗癌活性及其对曲妥珠单抗反应的调节作用。采用 qRT-PCR 微阵列分析,用有效浓度的他莫昔芬和曲妥珠单抗处理 BT-474、SK-BR-3 和 MCF-7 细胞。采用划痕愈合和 xCELLigence 阻抗测定法分别进行细胞迁移和侵袭分析。通过 WST-1 检测细胞活力,评估模拟转染和药物处理后细胞的活力。采用 Western blot 分析评估 miR-770-5p 对蛋白质及其磷酸化形式的调节作用。通过 TCGA 数据分析评估 miR-770-5p 的临床相关性。qRT-PCR 微阵列结果表明,miR-770-5p 以药物和细胞系独立的方式发生反应。miR-770-5p 的过表达通过调节 AKT 和 ERK 蛋白抑制了细胞的迁移和侵袭。此外,miR-770-5p 增强了曲妥珠单抗的疗效。因此,调节 miR-770-5p 的表达水平与曲妥珠单抗治疗相结合可能同时抑制 PI3K 和 MAPK 信号通路的下游元件,从而阻断 HER2+乳腺癌细胞的增殖、迁移和侵袭能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d6fe/6476517/77caed2eb56c/pone.0215894.g001.jpg

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