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

Hui Wang; Jiabin Chen; Shufen Zhang; Xiaoxiao Zheng; Shangzhi Xie; Jiayan Mao; Ying Cai; Xuemei Lu; Liqiang Hu; Jian Shen; Kequn Chai; Wei Chen

doi:10.1186/s12935-020-01284-x

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

Cancer Cell Int. 2020 Jun 19:20:258. doi: 10.1186/s12935-020-01284-x. eCollection 2020.

Authors

Hui Wang^#¹, Jiabin Chen^#², Shufen Zhang², Xiaoxiao Zheng², Shangzhi Xie², Jiayan Mao², Ying Cai², Xuemei Lu², Liqiang Hu², Jian Shen², Kequn Chai², Wei Chen²

Affiliations

¹ Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053 Zhejiang China.
² Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, No.234, Gucui Road, Hangzhou, 310012 Zhejiang China.

^# Contributed equally.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Autophagy; Chemoresistance; FBXW7; MiR-223; Non-small cell lung cancer (NSCLC).