Open Access

ARTICLE

miR-135a Confers Resistance to Gefitinib in Non-Small Cell Lung Cancer Cells by Upregulation of RAC1

Tingting Zhang^*1, Ning Wang^†1

* Department of Oncology, Shengli Oilfield Central Hospital, Dongying, Shandong, P.R. China
† Department of Thoracic Surgery, Shengli Oilfield Central Hospital, Dongying, Shandong, P.R. China
1 These authors provided equal contribution to this work.

Oncology Research 2018, 26(8), 1191-1200. https://doi.org/10.3727/096504018X15166204902353

Abstract

The EGFR tyrosine kinase inhibitor gefitinib is used in therapy for non-small cell lung cancer (NSCLC). However, the therapeutic efficacy of gefitinib is known to be impeded by mutations of EGFR. The aim of the present study was to reveal the role of miR-135a in gefitinib resistance of NSCLC cells. Human NSCLC cell lines, NCI-H1650 and NCI-H1975, were transfected with miR-135a mimic/inhibitor or miR-135a inhibitor plus pEX-RAC1 (a RAC1-expressing vector). The effects of miR-135a and RAC1 expression on cell viability, apoptosis, migration, and invasion were then detected. The transfected cells were exposed to 0–20 µM gefitinib, and cell viability was then detected at 48 h posttreatment. Western blot analysis was performed to detect the expression changes of main factors in the PI3K/AKT pathway. miR-135a overexpression promoted viability, migration, and invasion, but inhibited apoptosis of NCI-H1650 and NCI-H1975 cells. Cell viability was significantly reduced by gefitinib, and the LC₅₀ values of gefitinib in NCI-H1650 and NCI-H1795 cells were 0.845 and 0.667 µM, respectively. miR-135a overexpression could increase cell viability even under high concentrations of gefitinib. Rac1 was not predicted as a target of miR-135a, while miR-135a could upregulate the expression of RAC1. miR-135a promoted cell growth and metastasis and activated the PI3K/AKT signaling pathway via a RAC1-dependent manner. To conclude, this study demonstrated that miR-135a confers NSCLC cell resistance to gefitinib via upregulation of RAC1. Therapies designed to downregulate miR-135a may help NSCLC patients to overcome gefitinib resistance.

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