miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway.
miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/Akt signaling pathway.
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DOI：
10.3892/ijo.2016.3401
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发表时间：
2016-05
影响因子：
5.2
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Han J;Zhao F;Zhang J;Zhu H;Ma H;Li X;Peng L;Sun J;Chen Z
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）的获得性耐药，如吉非替尼和厄洛替尼，是治疗EGFR突变阳性非小细胞肺癌（NSCLC）的关键问题。最近的证据支持microRNA-223 （miR-223）在调节化疗药物敏感性中的作用，但其在NSCLC中对EGFR-TKIs的耐药中的作用尚不清楚。为此，我们研究了miR-223在厄洛替尼耐药中的作用，使用了两对tki敏感或耐药细胞系，PC9 vs PC9/ER, HCC827 vs HCC827/ER，以及PC9/CD133+，它们是来源于PC9细胞的肺癌干细胞样细胞。检测到miR-223在PC9/ER和PC9/CD133+细胞中的表达下调，并揭示了miR-233与这些细胞中胰岛素样生长因子1受体（IGF1R）的负相关。接下来，在miR-223稳定转染的PC9/ER和PC9/CD133+细胞中，IGF1R mRNA和p-Akt水平显著降低。然而，在这些细胞中过表达miR-223后，PC9/ER和PC9/CD133+细胞对厄洛替尼的敏感性部分恢复。在体内也观察到类似的结果。此外，在转染miR-223的细胞中，miR-223介导的IGF1R/PI3K/Akt信号通路的抑制可能被IGF1R激动剂逆转。我们的研究结果表明，miR-223的下调可以诱导PC9/ER和PC9/CD133+细胞中IGF1R/磷脂酰肌醇3-激酶(PI3K)/Akt通路的激活，可能是PC9/ER和PC9/CD133+细胞对厄洛替尼耐药的原因，这表明miR-223是克服EGFR-TKIs耐药的潜在治疗靶点。
Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, is a critical issue for the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). Recent evidence supports the role of microRNA-223 (miR-223) in modulating chemotherapeutic drug sensitivity, but its role in the resistance to EGFR-TKIs in NSCLC remains unclear. To this end, we investigated the involvement of miR-223 in erlotinib resistance, using two pairs of TKI-sensitive or resistant cell lines, PC9 vs PC9/ER, and HCC827 vs HCC827/ER, as well as PC9/CD133+, which are lung cancer stem-like cells derived from PC9 cells. Downregulation of miR-223 expression in PC9/ER and PC9/CD133+ cells was detected, and the reverse correlation of miR-233 and insulin-like growth factor 1 receptor (IGF1R) in these cells was also revealed. Next, levels of IGF1R mRNA and p-Akt were significantly reduced in miR-223 stably transfected PC9/ER and PC9/CD133+ cells. However, the sensitivity of PC9/ER and PC9/CD133+ cells to erlotinib was partially restored, after overexpression of miR-223 in those cells. Similar results were also observed in vivo. Furthermore, miR-223-mediated inhibition of the IGF1R/PI3K/Akt signaling pathway may have been reversed by the agonist of IGF1R in miR-223 transfected cells. Our findings indicated that downregulation of miR-223, which can induce activation of the IGF1R/phosphatidylinositol 3-kinase (PI3K)/Akt pathway in PC9/ER and PC9/CD133+ cells, may be responsible for the resistance of PC9/ER and PC9/CD133+ cells to erlotinib, suggesting that miR-223 is a potential therapeutic target for overcoming EGFR-TKIs resistance.