Abstract
Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly induced in gefitinib-resistant lung cancer cells. To understand the role and mechanism of miR-196a in TKI resistance, we found that miR-196a-forced expression alone increased cell resistance to gefitinib treatment in vitro and in vivo by inducing cell proliferation and inhibiting cell apoptosis. We identified the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) bound to the promoter region of miR-196a and induced miR-196a expression at the transcriptional level. NRF2-forced expression also significantly increased expression levels of miR-196a, and was an upstream inducer of miR-196a to mediate gefitinib resistance. We also found that glycolipid transfer protein (GLTP) was a functional direct target of miR-196a, and downregulation of GLTP by miR-196a was responsible for gefitinib resistance. GLTP overexpression alone was sufficient to increase the sensitivity of lung cancer cells to gefitinib treatment. Our studies identified a new role and mechanism of NRF2/miR-196a/GLTP pathway in TKI resistance and lung tumor development, which may be used as a new biomarker (s) for TKI resistance or as a new therapeutic target in the future.
Highlights
Lung cancer is one of the most serious human malignant tumors
The correlation of the patient survival and miR-196a levels in lung adenocarcinoma (LUAD) was analyzed using The Cancer Genome Atlas (TCGA) database; the result showed that patients with higher miR-196a expression levels had significantly lower overall survival rates (Figure S1c). These results indicated that higher expression levels of miR-196a in lung cancer cells were associated with gefitinib resistance, which indicated that miR-196a may be a potential therapeutic target to overcome gefitinib resistance, which is to be investigated in the future
These results indicated that glycolipid transfer protein (GLTP) played an important role in the malignant stages, which was suggested as a functional target of miR-196a to regulate gefitinib resistance in lung adenocarcinoma
Summary
Lung cancer is one of the most serious human malignant tumors. The morbidity and mortality of lung cancer are much higher than most malignant cancers [1]. Our results showed that the three candidate genes were all downregulated in PC-9-G cells (Figure 4c and Figure S3b,c) and tumor tissues (Figure S3f) These results indicated that all three target genes were probably involved in tumor drug resistance or promoted the occurrence of lung cancer, but only GLTP levels were decreased significantly with p < 0.01 in miR-196a overexpression cells (Figure 4d). TCGA database analysis showed that the lung cancer patients with lower expression levels of GLTP had a shorter time of survival than those with higher levels of GLTP (Figure 4j) These results indicated that GLTP played an important role in the malignant stages, which was suggested as a functional target of miR-196a to regulate gefitinib resistance in lung adenocarcinoma.
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