Abstract
Gefitinib resistance is one of the major obstacles for the treatment of lung adenocarcinoma (LAD). The present study aimed to investigate the effects of the long non-coding RNA (lncRNA), small nucleolar RNA host gene 5SNHG5 on gefitinib resistance in LAD and explore the underlying mechanisms. The quantitative real-time PCR (qRT-PCR) results showed that SNHG5 expression was significantly down-regulated in LAD patients with acquired gefitinib resistance and gefitinib resistant LAD cell lines. SNHG5 overexpression sensitized gefitinib resistant LAD cells to gefitinib treatment, while knockdown of SNHG5 rendered gefitinib sensitive LAD cells to gefitinib treatment. Bioinformatics analysis showed that SNHG5 exerted its function through interaction with miR-377, which was further confirmed by luciferase reporter assay in 293T cells. Overexpression of SNHG5 suppressed the expression of miR-377, while the knockdown of SNHG5 increased the miR-377 expression. MiR-377 expression was significantly up-regulated in LAD specimens with acquired gefitinib resistance and was negatively correlated with SNHG5 expression. In addition, CASP1 was predicted as a downstream target of miR-377. Overexpression of miR-377 suppressed the expression of CASP1 in PC9 cells and knockdown of miR-377 increased the CASP1 expression in PC9GR cells. In vitro functional assay showed that knockdown of CASP1 in SNHG5-overexpressed PC9GR cells abolished their gefitinib resistance. Overall, the present study demonstrated, for the first time, that the SNHG5/miR-377/CASP1 axis functions as an important role in LAD cells gefitinib resistance and potentially contributes to the improvement of LAD diagnosis and therapy.
Highlights
Lung cancer has become one of the most common malignancies and the leading cause of cancer-associated mortality worldwide
We measured the mRNA expression of small nucleolar RNA host gene 5 (SNHG5) by RT-PCR in eight matched Lung adenocarcinoma (LAD) patients’ specimens, and found that SNHG5 expression was down-regulated in patients with acquired resistance (Figure 1C)
We found that SNHG5 expression was significantly down-regulated in LAD patients and LAD cell lines with acquired gefitinib resistance
Summary
Lung cancer has become one of the most common malignancies and the leading cause of cancer-associated mortality worldwide. Lung adenocarcinoma (LAD) is the most common type of primary lung cancer and is usually diagnosed at an advanced stage [1]. Treatment options available for NSCLC include surgery, radiation, chemotherapy, and biological therapy [2]. Gefitinib is clinically used for the treatment of chemoresistant NSCLC patients, which is a selective inhibitor of epidermal growth factor, a growth factor that plays a pivotal role in the control of cell growth, apoptosis, and angiogenesis [3]. Acquired resistance to targetted therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, occurs inevitably in almost all the NSCLC patients [4]. It is vital to explore novel strategies to restore sensitivity to gefitinib [5]
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