miR-126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells
miR-126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT/mTOR pathway in breast cancer cells
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DOI：
10.1111/jcmm.15396
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发表时间：
2020-05-15
影响因子：
5.3
通讯作者：
Tong Jing-Shan
中科院分区：
文献类型：
--
作者：
Fu Rao;Tong Jing-Shan
MicroRNAs （miRNAs）已被发现在耐药性中发挥关键作用。在目前的研究中，我们旨在探索miR-126在乳腺癌细胞曲妥珠单抗耐药中的潜在作用。我们发现，曲妥珠单抗耐药细胞系SKBR3/TR和BT474/TR miR-126的表达水平较低，迁移和侵袭能力增强。miR-126模拟物的异位表达降低了曲妥珠单抗耐药细胞的耐药、侵袭和动员能力。相比之下，在SKBR3亲本细胞中抑制miR-126具有相反的作用，即增加对曲妥珠单抗的耐药性以及侵袭和迁移。还发现miR-126在乳腺癌细胞中直接靶向PIK3R2。PIK3R2敲低细胞对曲妥珠单抗的耐药降低，而PIK3R2过表达增加曲妥珠单抗耐药。此外，我们的研究结果表明，在曲妥珠单抗耐药细胞中，miR-126的过表达降低了对曲妥珠单抗的耐药性，并且抑制PIK3R2/PI3K/AKT/mTOR信号通路参与了这种作用。在体内，SKBR3/TR细胞也显示出对miR-126介导的曲妥珠单抗的敏感性增加。综上所述，上述研究结果表明，miR-126过表达或下调其靶基因可能是克服乳腺癌细胞曲妥珠单抗耐药的潜在途径。
MicroRNAs (miRNAs) have been found to play a key role in drug resistance. In the current study, we aimed to explore the potential role of miR-126 in trastuzumab resistance in breast cancer cells. We found that the trastuzumab-resistant cell lines SKBR3/TR and BT474/TR had low expression of miR-126 and increased ability to migrate and invade. The resistance, invasion and mobilization abilities of the cells resistant to trastuzumab were reduced by ectopic expression of miR-126 mimics. In comparison, inhibition of miR-126 in SKBR3 parental cells had the opposite effect of an increased resistance to trastuzumab as well as invasion and migration. It was also found that miR-126 directly targets PIK3R2 in breast cancer cells. PIK3R2-knockdown cells showed decreased resistance to trastuzumab, while overexpression of PIK3R2 increased trastuzumab resistance. In addition, our finding showed that overexpression of miR-126 reduced resistance to trastuzumab in the trastuzumab-resistant cells and that inhibition of the PIK3R2/PI3K/AKT/mTOR signalling pathway was involved in this effect. SKBR3/TR cells also showed increased sensitivity to trastuzumab mediated by miR-126 in vivo. In conclusion, the above findings demonstrated that overexpression of miR-126 or down-regulation of its target gene may be a potential approach to overcome trastuzumab resistance in breast cancer cells.