Zheng Fushuang, Zhang Hongyan, Lu Jibin
Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China.
J Thorac Dis. 2019 Dec;11(12):5535-5546. doi: 10.21037/jtd.2019.11.25.
Non-small cell lung cancer (NSCLC) accounts for about 80-85% of lung cancers. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib are considered the best choice for first-line treatment for the patients with NSCLC harboring EGFR-activating alterations. Nonetheless, 10-30% of patients may not obtain an objective response and may also experience rapid progression. The aim of our research, based on the integrative bioinformatics review, was to identify the possible miRNAs involved in gefitinib resistance.
A gefitinib-resistant network composed of 15 miRNAs and 34 targets were constructed by using the bioinformatics analyses of three microarray datasets. Of these miRNAs, effects of miR-342-3p on gefitinib resistance were investigated on a gefitinib-resistant cell model (A549/GR and PC/GR cells).
We reported that over-expression of miR-342-3p could significantly increase the resistance to gefitinib of A549/GR and PC9/GR cells and vice versa. Then, we recognized CPA4 as a target of hsa-miR-342-3p by a luciferase reporter assay. The increase in hsa-miR-342-3p levels led to a significant reduction in CPA4 protein expression. However, the opposite results were observed upon miR-342-3p knockdown. Finally, we found that enforced CPA4 expression partially reversed miR-342-3p effects in A549/GR cells.
Collectively, these findings suggest that the upregulation of miR-342-3p contributes to gefitinib resistance by targeting CPA4, which may serve as a potential treatment option to overcome gefitinib resistance in patients with NSCLC.
非小细胞肺癌（NSCLC）约占肺癌的80 - 85%。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）如吉非替尼被认为是一线治疗伴有EGFR激活改变的NSCLC患者的最佳选择。尽管如此，10 - 30%的患者可能无法获得客观缓解，并且可能还会经历快速进展。基于综合生物信息学综述，我们研究的目的是确定可能参与吉非替尼耐药的微小RNA（miRNA）。
通过对三个微阵列数据集进行生物信息学分析，构建了一个由15个miRNA和34个靶标组成的吉非替尼耐药网络。在这些miRNA中，在吉非替尼耐药细胞模型（A549/GR和PC/GR细胞）上研究了miR-342-3p对吉非替尼耐药性的影响。
我们报道miR-342-3p的过表达可显著增加A549/GR和PC9/GR细胞对吉非替尼的耐药性，反之亦然。然后，通过荧光素酶报告基因检测，我们确定CPA4是hsa-miR-342-3p的一个靶标。hsa-miR-342-3p水平的升高导致CPA4蛋白表达显著降低。然而，在敲低miR-342-3p后观察到相反的结果。最后，我们发现强制表达CPA4可部分逆转A549/GR细胞中miR-342-3p的作用。
总的来说，这些发现表明miR-342-3p的上调通过靶向CPA4导致吉非替尼耐药，这可能是克服NSCLC患者吉非替尼耐药的一种潜在治疗选择。
