Abstract
BackgroundCisplatin is widely used as a first-line treatment for non-small cell lung cancer (NSCLC), but chemoresistance remains a major clinical obstacle for efficient use. As a microRNA, miR-223 was reported to promote the doxorubicin resistance of NSCLC. However, whether miR-223 is also involved in cisplatin resistance of NSCLC and the mechanism miR-223 involved in drug resistance is unclear. Accumulated evidence has shown that abnormal autophagy is associated with tumor chemoresistance. The study aimed to study the role of miR-223 on cisplatin sensitivity in NSCLC and uncover the potential mechanisms.MethodsNSCLC cells transfected with mimic or inhibitor for miR-223 was assayed for chemoresistance in vitro. MiR-223 expression was assessed by quantitative real-time PCR (qRT-PCR). Western blot were used to study the expression level of F-box/WD repeat-containing protein 7 (FBXW7) and autophagy-related protein. The effect of miR-223 on cisplatin sensitivity was examined by using CCK-8, EdU assays and Autophagic flux assay. Luciferase assays, EdU assays and small interfering RNA were performed to identify the targets of miR-223 and the mechanism by which it promotes treatment resistance. Xenograft models were established to investigate the effect of mir-223 on cisplatin sensitivity.ResultsIn the present study, we found that the level of miR-223 was significantly positively correlated with cisplatin resistance. MiR-223 overexpression made NSCLC cells resistant to cisplatin treatment. We further found that autophagy mediated miR-223-mediated cisplatin resistance in NSCLC cells. Further mechanistic research demonstrated that miR-223 directly targeted FBXW7. The overexpression of miR-223 could inhibit the level of FBXW7 protein expression, thus promoting autophagy and making NSCLC cells resistant to cisplatin. Finally, we confirmed the increased effect of cisplatin sensitivity by miR-223 Antagomir in xenograft models of NSCLC.ConclusionsOur results demonstrate that miR-223 could enhance autophagy by targeting FBXW7 in NSCLC cells. Inhibition of autophagy by miR-223 knockdown provides a novel treatment strategy to alleviate cisplatin resistance in NSCLC.
Highlights
Cisplatin is widely used as a first-line treatment for non-small cell lung cancer (NSCLC), but chemoresistance remains a major clinical obstacle for efficient use
The level of miR‐223 was positively correlated with cisplatin resistance in Non-small cell lung cancer (NSCLC) cells To investigate the biological role of miR-223 in NSCLC cisplatin resistance, we first quantified the level of miR223 in four NSCLC cells
The cell viability in each cell line represented an positive trend with the level of miR-223 (Fig. 1b); NSCLC cells with high miR-223 levels were more resistant to cisplatin
Summary
Cisplatin is widely used as a first-line treatment for non-small cell lung cancer (NSCLC), but chemoresistance remains a major clinical obstacle for efficient use. As a microRNA, miR-223 was reported to promote the doxorubicin resistance of NSCLC. Cisplatin-based traditional chemotherapy and molecular targeting drug therapy have greatly improved the prognosis and quality of life in NSCLC patients [4, 5]. Liang et al reported that platelet-secreted microvesicles (P-MVs) can promote lung cancer cell invasion via targeting the tumor suppressor, EPB41L3 [17]. Zhou et al reported that miR-223 inhibits tumor development of NSCLC and sensitizes A549 cells to gefitinib via targeting E2F1 [18]. Another study showed that miR-223 could induce doxorubicin resistance through targeting F-box/ WD repeat-containing protein 7 (FBXW7)-mediated epithelial mesenchymal transition in NSCLC cells [20]. Additional studies are essential to further uncover the role of miR-223 in the development and drug resistance in NSCLC
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