MiR-30a-5p Overexpression May Overcome EGFR-Inhibitor Resistance through Regulating PI3K/AKT Signaling Pathway in Non-small Cell Lung Cancer Cell Lines.
MiR-30a-5p Overexpression May Overcome EGFR-Inhibitor Resistance through Regulating PI3K/AKT Signaling Pathway in Non-small Cell Lung Cancer Cell Lines.
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miR-30a-5p过表达可以通过调节非小细胞肺癌细胞系中的PI3K/AKT信号通路来克服EGFR抑制剂的耐药性。
DOI：
10.3389/fgene.2016.00197
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发表时间：
2016
影响因子：
3.7
通讯作者：
Chan LW
中科院分区：
文献类型：
--
作者：
Meng F;Wang F;Wang L;Wong SC;Cho WC;Chan LW
肺癌是世界范围内最常见的致命疾病之一，其中大部分是非小细胞肺癌（NSCLC）。表皮生长因子受体（EGFR）突变型NSCLC经常对EGFR酪氨酸激酶抑制剂（EGFR-TKI）治疗产生应答，如吉非替尼和厄洛替尼，但获得性耐药的发展限制了其效用。已经探索了多种抗性机制，例如，与EGFR共享相似下游途径的替代性酪氨酸激酶受体（TKR）的激活。microRNA（miRNAs）是一类短的内源性非编码RNA分子，调控靶基因的表达。在本研究中，我们探索了miR-30 a-5 p在靶向EGFR和胰岛素样生长因子受体-1（IGF-1 R）信号通路以克服耐药性方面的潜力。IGF-1 R是一种酪氨酸激酶受体，其具有相同的EGFR下游分子，包括磷脂酰肌醇3激酶（PI 3 K）和蛋白激酶B（AKT）。在这项工作中，设计了一项在两种吉非替尼耐药NSCLC细胞系H460和H1975中使用EGFR抑制剂（吉非替尼）、IGF-1 R抑制剂（NVP-AEW 541）和miRNA模拟物的体外研究。我们发现，EGFR和IGF-1 R抑制剂的组合显着降低磷酸化AKT（p-AKT）的表达水平相比，在这两个细胞系的对照组。磷酸肌醇-3-激酶调节亚基2（PIK 3R 2）的敲低与EGFR和IGF-1 R的双重抑制具有相同的效果，以减少信号通路中p-AKT的表达。过表达miR-30 a-5 p可显著降低PI 3 K调节亚基（PIK 3R 2）的表达，进一步诱导细胞凋亡，抑制细胞侵袭和迁移特性。因此，miR-30 a-5 p可能在克服对EGFR-TKI的获得性耐药性方面发挥重要作用，并为建立新的癌症治疗方法提供有用的信息。
Lung cancer is one of the most common deadly diseases worldwide, most of which is non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutant NSCLCs frequently respond to the EGFR tyrosine kinase inhibitors (EGFR-TKIs) treatment, such as Gefitinib and Erlotinib, but the development of acquired resistance limits the utility. Multiple resistance mechanisms have been explored, e.g., the activation of alternative tyrosine kinase receptors (TKRs) sharing similar downstream pathways to EGFR. MicroRNAs (miRNAs) are short, endogenous and non-coding RNA molecules, regulating the target gene expression. In this study, we explored the potential of miR-30a-5p in targeting the EGFR and insulin-like growth factor receptor-1 (IGF-1R) signaling pathways to overcome the drug resistance. IGF-1R is one of the tyrosine kinase receptors that share the same EGFR downstream molecules, including phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT). In this work, an in vitro study was designed using EGFR inhibitor (Gefitinib), IGF-1R inhibitor (NVP-AEW541), and miRNA mimics in two Gefitinib-resistant NSCLC cell lines, H460 and H1975. We found that the combination of EGFR and IGF-1R inhibitors significantly decreased the phosphorylated AKT (p-AKT) expression levels compared to the control group in these two cell lines. Knockdown of phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) had the same effect with the dual inhibition of EGFR and IGF-1R to reduce the expression of p-AKT in the signaling pathway. Overexpression of miR-30a-5p significantly reduced the expression of the PI3K regulatory subunit (PIK3R2) to further induce cell apoptosis, and inhibit cell invasion and migration properties. Hence, miR-30a-5p may play vital roles in overcoming the acquired resistance to EGFR-TKIs, and provide useful information for establishing novel cancer treatment.
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影响因子：
5.3
作者：
Yeo, Chang Dong;Park, Ki Hoon;Kim, Tae-Jung
通讯作者：
Kim, Tae-Jung
影响因子：
3.7
作者：
Zhao J;Kelnar K;Bader AG
通讯作者：
Bader AG
影响因子：
3.7
作者：
Wang F;Meng F;Wang L;Wong SC;Cho WC;Chan LW
通讯作者：
Chan LW
影响因子：
4.8
作者：
Kurosu, H;Maehama, T;Katada, T
通讯作者：
Katada, T
影响因子：
30.8
作者：
Krek, A;Grun, D;Rajewsky, N
通讯作者：
Rajewsky, N