Identification of potential microRNAs and their targets in promoting gefitinib resistance by integrative network analysis.

Background: 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.

Method: 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).

Results: 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.

Conclusions: 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.