All lung cancers patients with epidermal growth factor receptor (EGFR) mutation inevitably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In up to 30% of cases, the mechanism underlying acquired resistance remains unknown. MicroRNAs (miRNAs) is a group of small non-coding RNAs commonly dysregulated in human cancers and have been implicated in therapy resistance. The aim of this study was to understand the roles of novel miRNAs in acquired EGFR TKI resistance in EGFR-mutant non-small cell lung cancer (NSCLC). Here, we reported the evidence of miR-483-3p silencing and epithelial-to-mesenchymal transition (EMT) phenotype in both in vitro and in vivo EGFR-mutant NSCLC models with acquired resistance to gefitinib. In those tumor models, forced expression of miR-483-3p efficiently increased sensitivity of gefitinib-resistant lung cancer cells to gefitinib by inhibiting proliferation and promoting apoptosis. Moreover, miR-483-3p reversed EMT and inhibited migration, invasion, and metastasis of gefitinib-resistant lung cancer cells. Mechanistically, miR-483-3p directly targeted integrin β3, and thus repressed downstream FAK/Erk signaling pathway. Furthermore, the silencing of miR-483-3p in gefitinib-resistant lung cancer cells was due to hypermethylation of its own promoter. Taken together, our data identify miR-483-3p as a promising target for combination therapy to overcome acquired EGFR TKI resistance in EGFR-mutant NSCLC.

中文翻译：

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通过靶向整联蛋白β3，miR-483-3p的表观遗传沉默可促进EGFR突变型NSCLC中获得性吉非替尼耐药性和EMT。

所有患有表皮生长因子受体（EGFR）突变的肺癌患者都不可避免地产生对EGFR酪氨酸激酶抑制剂（TKI）的获得性耐药。在多达30％的情况下，获得性耐药的潜在机制仍然未知。微小RNA（miRNA）是一组在人类癌症中通常失调的小型非编码RNA，并与治疗耐药性有关。本研究的目的是了解新型miRNA在EGFR突变型非小细胞肺癌（NSCLC）中获得性EGFR TKI抗性中的作用。在这里，我们报道了对吉非替尼具有耐药性的体外和体内EGFR突变NSCLC模型中miR-483-3p沉默和上皮-间质转化（EMT）表型的证据。在那些肿瘤模型中 通过抑制miR-483-3p的增殖和促进细胞凋亡，miR-483-3p的强制表达有效提高了对吉非替尼耐药的肺癌细胞对吉非替尼的敏感性。此外，miR-483-3p逆转了EMT并抑制了对吉非替尼耐药的肺癌细胞的迁移，侵袭和转移。机械上，miR-483-3p直接靶向整联蛋白β3，从而抑制了下游FAK / Erk信号通路。此外，耐吉非替尼的肺癌细胞中miR-483-3p的沉默归因于其自身启动子的高度甲基化。两者合计，我们的数据确定miR-483-3p作为克服EGFR突变型NSCLC中获得性EGFR TKI耐药性的联合治疗的有希望的靶标。吉非替尼耐药的肺癌细胞的转移和转移。机械上，miR-483-3p直接靶向整联蛋白β3，从而抑制了下游FAK / Erk信号通路。此外，耐吉非替尼的肺癌细胞中miR-483-3p的沉默归因于其自身启动子的高度甲基化。两者合计，我们的数据确定miR-483-3p作为克服EGFR突变型NSCLC中获得性EGFR TKI耐药性的联合治疗的有希望的靶标。吉非替尼耐药的肺癌细胞的转移和转移。机械上，miR-483-3p直接靶向整联蛋白β3，从而抑制了下游FAK / Erk信号通路。此外，耐吉非替尼的肺癌细胞中miR-483-3p的沉默归因于其自身启动子的高度甲基化。两者合计，我们的数据确定miR-483-3p作为克服EGFR突变型NSCLC中获得性EGFR TKI耐药性的联合治疗的有希望的靶标。