MiR-223 regulates autophagy associated with cisplatin resistance by targeting FBXW7 in human non-small cell lung cancer

• Published in: Cancer cell international Vol. 20; no. 1; p. 258
• Main Authors: Wang, Hui, Chen, Jiabin, Zhang, Shufen, Zheng, Xiaoxiao, Xie, Shangzhi, Mao, Jiayan, Cai, Ying, Lu, Xuemei, Hu, Liqiang, Shen, Jian, Chai, Kequn, Chen, Wei
• Format: Journal Article
• Language: English
• Published: England BioMed Central 19.06.2020; BMC
• Subjects: Antibodies; Apoptosis; Autophagy; Cancer therapies; Cdc4 protein; Chemoresistance; Chemotherapy; Cholecystokinin; Cisplatin; Doxorubicin; Drug resistance; FBXW7; Flow cytometry; Lung cancer; Medical prognosis; MicroRNAs; MiR-223; miRNA; Non-small cell lung cancer (NSCLC); Non-small cell lung carcinoma; Phagocytosis; Primary Research; Proteins; siRNA; Small cell lung carcinoma; Studies; Xenografts; United States > US; China; Japan; MiR-223; FBXW7; Autophagy; Chemoresistance; Non-small cell lung cancer (NSCLC)
• ISSN: 1475-2867; 1475-2867
• DOI: 10.1186/s12935-020-01284-x

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. 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. NSCLC 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. In 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. Our 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.