Department of Thoracic Surgery, Peking Union Medical College Hospital (PUMCH), Beijing 100730, P.R. China.
Oncol Rep. 2017 Nov;38(5):3064-3070. doi: 10.3892/or.2017.5938. Epub 2017 Sep 4.
Epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKIs) have become first-line drugs used for non-small cell lung cancer (NSCLC) treatment. However, drug resistance to EGFR-TKIs will be developed inevitably due to the repeated use of these drugs. In the present study, we isolated cancer stem cells (CSCs) from the PC9 NSCLC cell line. We then observed that the PC9 CSCs showed significant resistance to erlotinib compared with the PC9 non-CSCs. Erlotinib failed to suppress the phosphorylation of PI3K and AKT in PC9 CSCs, although the EGFR was inhibited sufficiently. Mechanically, we observed aberrant upregulation of microRNA-23a (miR-23a) and downregulation of PTEN in PC9 CSCs compared to PC9 non-CSCs. Luciferase reporter assays proved that PTEN was the target of miR-23a in PC9 CSCs. Furthermore, knockdown of miR-23a enhanced the antitumor effect of erlotinib by increasing the expression of PTEN. In addition, transfection with miR-23a inhibitors promoted the erlotinib-dependent inhibition of PI3K/AKT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs. These results propose that upregulation of miR-23a is a potential mechanism associated with resistance to EGFR-TKIs in lung cancer stem cells. Inhibition of miR-23a serves as a novel therapeutic strategy to eliminate the EGFR-TKIs resistance of lung cancer stem cells.
表皮生长因子受体靶向酪氨酸激酶抑制剂（EGFR-TKIs）已成为治疗非小细胞肺癌（NSCLC）的一线药物。然而，由于这些药物的反复使用，不可避免地会产生对 EGFR-TKIs 的耐药性。在本研究中，我们从 PC9 NSCLC 细胞系中分离出癌症干细胞（CSCs）。然后我们观察到，与 PC9 非 CSCs 相比，PC9 CSCs 对厄洛替尼表现出明显的耐药性。厄洛替尼虽然足以抑制 EGFR 的磷酸化，但未能抑制 PC9 CSCs 中 PI3K 和 AKT 的磷酸化。从机制上讲，与 PC9 非 CSCs 相比，我们观察到 PC9 CSCs 中 microRNA-23a（miR-23a）的异常上调和 PTEN 的下调。荧光素酶报告基因检测证实 PTEN 是 PC9 CSCs 中 miR-23a 的靶基因。此外，miR-23a 的敲低通过增加 PTEN 的表达增强了厄洛替尼的抗肿瘤作用。此外，miR-23a 抑制剂的转染促进了 PI3K/AKT 通路对厄洛替尼的依赖性抑制，从而抑制了 PC9 CSCs 的增殖并诱导其凋亡。这些结果表明，miR-23a 的上调是与肺癌干细胞对 EGFR-TKIs 耐药相关的潜在机制。抑制 miR-23a 可作为消除肺癌干细胞对 EGFR-TKIs 耐药性的新治疗策略。
