Abstract
BackgroundThis study aims to investigate the mechanism underlying the high level of long non-coding RNA FOXD3-AS1 in cisplatin-resistant NSCLC cells.MethodsCisplatin-resistant cells were generated from A549 cells. CCK-8 were used to evaluate cell proliferation. The FOXD3-AS1, miR-127-3p, MDM2 and MRP1 mRNA expression levels were confirmed by qRT-PCR. Protein levels of MDM2 and MRP1 were determined by western blot assay. Luciferase reporter and RNA pull-down assays were evaluated the relationship between miR-127-3p and FOXD3-AS1/MDM2. In vivo tumor growth was evaluated in a xenograft nude mice model.ResultsFOXD3-AS1 was up-regulated in cisplatin-resistant NSCLC cells (A549/DDP and H1299/DDP cells) in comparison with their parental cell lines. Overexpression of FOXD3-AS1 promoted cisplatin-resistance in A549 and H1299 cells; while FOXD3-AS1 knockdown sensitized A549/DDP and H1299/DDP cells to cisplatin treatment. FOXD3-AS1 regulated miR-127-3p expression by acting as a competing endogenous RNA, and miR-127-3p repressed MDM2 expression via targeting the 3′UTR. MiR-127-3p overexpression and MDM2 knockdown both increased the chemo-sensitivity in A549/DDP cells; while miR-127-3p knockdown and MDM2 overexpression both promoted chemoresistance in A549 cells. Further rescue experiments revealed that miR-127-3p knockdown or MDM2 overexpression counteracted the suppressive effects of FOXD3-AS1 knockdown on chemo-resistance and MRP1 expression in A549/DDP cells. In vivo studies showed that FOXD3-AS1 knockdown potentiated the antitumor effects of cisplatin treatment. Inspection of clinical samples showed the upregulation of FOXD3-AS1 and MDM2, and down-regulation of miR-127-3p in NSCLC tissues compared to normal adjacent tissues.ConclusionIn conclusion, our results suggest that LncRNA FOXD3-AS1 promotes chemo-resistance of NSCLC cells via directly acting on miR-127-3p/MDM2 axis. Our findings may provide novel perspectives for the treatment of NSCLC in patients resistant to chemotherapy.
Highlights
This study aims to investigate the mechanism underlying the high level of long non-coding RNA FOXD3-AS1 in cisplatin-resistant Non-small cell lung cancer (NSCLC) cells
The FOXD3-AS1 expression was up-regulated in NSCLC cell lines (A549 and H1299) in comparison with Normal human lung bronchial epithelial cells (NHBE)
Cells (Fig. 1a), and further comparison showed that FOXD3-AS1 expression was up-regulated in DDP-resistant cell lines (A549/DDP and H1299/DDP) in comparison with their parental cells lines, respectively (Fig. 1a)
Summary
This study aims to investigate the mechanism underlying the high level of long non-coding RNA FOXD3-AS1 in cisplatin-resistant NSCLC cells. Lung cancer represents one of the most deadly tumor malignancies with patients having very low overall survival rate, due to the high metastasis of this disease [1, 2]. Non-small cell lung cancer (NSCLC) is the main type of lung and accounts for more than 80% of all the. Chemotherapy and surgical resection are the main strategies for treating NSCLC, and cisplatin-based chemotherapy has been widely used in treating NSCLC [3]. The development of cisplatin resistance has been a major obstacle in treating NSCLC [5, 6]. Exploration of novel strategies to promote cisplatin sensitivity is urgent for us to have a better control of this malignancy
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