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miR-216a-5p inhibits malignant progression in small cell lung cancer: involvement of the Bcl-2 family proteins

Authors Sun Y, Hu B, Wang Y, Li Z, Wu J, Yang Y, Wei Y, Peng X, Chen H, Chen RQ, Jiang P, Fang S, Yu Z, Guo L

Received 27 June 2018

Accepted for publication 23 August 2018

Published 18 October 2018 Volume 2018:10 Pages 4735—4745

DOI https://doi.org/10.2147/CMAR.S178380

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 3

Editor who approved publication: Dr Beicheng Sun


Yanqin Sun,1,* Bingshuang Hu,2,* Yanhong Wang,3 Zhen Li,1 Jingfang Wu,4 Yunchu Yang,4 Yue Wei,5 Xiaofeng Peng,5 Hongling Chen,5 Rongqi Chen,5 Pingyan Jiang,5 Sixian Fang,5 Zhiwu Yu,6 Linlang Guo4

1Department of Pathology, Guangdong Medical University, Dongguan, China; 2Department of Radiotherapy, Zhongshan People’s Hospital, Zhongshan, China; 3Department of Gynecology, Jinxiang People’s Hospital, Jining, China; 4Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; 5College of Pharmacy, Guangdong Medical University, Dongguan, China; 6Division of Laboratory Science, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China

*These authors contributed equally to this work

Objective: microRNAs are regulatory molecules regarded as important in the pathogenesis of different types of tumors. microRNA-216a (miR-216a-5p) has been identified as a tumor suppressor in multiple malignancies. However, the role of miR-216a-5p in the pathogenesis of small cell lung cancer (SCLC) remains obscure. The objective of this study was to investigate the role of the miR-216a-5p/Bcl-2 axis in SCLC pathogenesis.
Materials and methods: All the experimental methods used were as follows: microarray analysis, cell culture, transient, and stable gene transfection; real-time fluorescence PCR; Western blot; flow cytometry for cell cycle analysis; in vitro proliferation assay; in vitro wound healing experiment; in vivo xenograft model in nude mice; and dual luciferase reporter assay. All statistical analyses were carried out using GraphPad Prism 7 software. Statistical significance was analyzed by Student’s t-test or one-way ANOVA. P <0.05 (typically compared with the negative control group) was considered as significant and is marked with an asterisk in the figures.
Results: In this study, we observed that miR-216a-5p is downregulated in SCLC cell lines compared to that in the normal human bronchial epithelial cell line 16-HBE. In vitro and in vivo experiments demonstrate that upregulation of miR-216a-5p significantly decreased cell growth and migration and its downregulation increased SCLC cell proliferation and migration and influenced the cell cycle. Using bioinformatics analyses, we predicted that the important antiapoptotic gene Bcl-2 is targeted by miR-216a-5p, and we identified a functional miR-216a-5p binding site in the 3′-UTR of Bcl-2 using luciferase reporter assay. Furthermore, we determined that suppression of miR-216a-5p modulated the expression of Bcl-2, Bax, and Bad proteins (Bcl-2 family proteins), while Bcl-2 knockdown abrogated the effect of miR-216a-5p downregulation on cell proliferation, cell migration, and the cell cycle.
Conclusion: Taken together, these findings suggest that miR-216a-5p regulates SCLC biology via Bcl-2 family proteins. Therefore, our study highlights the role of the miR-216a-5p/Bcl-2 axis in SCLC pathogenesis.

Keywords: pathogenesis, miR-216a-5p, Bcl-2, SCLC

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