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The inhibitive effect of sh-HIF1A-AS2 on the proliferation, invasion, and pathological damage of breast cancer via targeting miR-548c-3p through regulating HIF-1α/VEGF pathway in vitro and vivo

Authors Guo X, Lee S, Cao P

Received 26 October 2018

Accepted for publication 25 December 2018

Published 24 January 2019 Volume 2019:12 Pages 825—834

DOI https://doi.org/10.2147/OTT.S192377

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Professor Jianmin Xu


Xiao Guo,1,* Shenghai Lee,2,* Peilong Cao3

1Department of Breast Surgery, Central Clinical College of Gynecology Obstetrics, Tianjin Medical University, Tianjin 300110, China; 2Department of Surgery, Zhaoqing Medical College, Zhaoqing, Guangdong 526020, China; 3Department of Pathology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shanxi 710061, China

*These authors contributed equally to this work

Background: Breast cancer (BC) has been the commonest malignant tumor with a low survival rate among woman. Long non-coding RNA hypoxia-inducible factor-1 alpha antisense RNA-2 (HIF1A-AS2) was correlated with various cancers.
Purpose: The study aimed to investigate the roles and related underlying molecular mechanisms of HIF1A-AS2 in BC.
Material and methods: Target relationships were speculated by Targetscan 7.0 and confirmed by dual luciferase reporter assay. Proteins levels were monitored by RT-qPCR, Western blot and immunohistochemistry assays. CCK-8 assay, SA-β-gal staining and transwell assay were used to detect proliferation, senescence and invasion, respectively. Xenograft nude mice were put into use to evaluate the tumor growth and motility.
Results: The present study exhibited that HIF1A-AS2 and hypoxia-inducible factor-1 alpha (HIF-1α) were upregulated while miR-548c-3p was downregulated in MDA-MB-231, MCF-7, ZR-75-1, and BT-549 BC cell lines. Bioinformatics analysis showed HIF1A-AS2 and HIF-1α were two targets of miR-548c-3p, and the target relationship was further confirmed by dual luciferase reporter assay. Moreover, knockdown of HIF1A-AS2 by shRNA (sh-HIF1A-AS2) markedly elevated miR-548c-3p level, and the enhanced miR-548c-3p noticeably suppressed cell proliferation, invasion, and epithelial–mesenchymal transition, and promoted senescence in vitro. In addition, overexpression of HIF-1α promoted MCF-7 cell invasion. Intriguingly, low expression of HIF1A-AS2 reduced HIF-1α level by upregulating the expression of miR-548c-3p. Furthermore, experiment in xenograft nude mice has indicated that sh-HIF1A-AS2 inhibited tumor growth and motility by targeting miR-548c-3p through regulating HIF-1α/vascular endothelial growth factor (VEGF) pathway in vivo.
Conclusion: The inhibitive effect of HIF-1α/VEGF pathway by sh-HIF1A-AS2 through targeting miR-548c-3p plays crucial regulatory roles in BC. Therefore, designing targeted drugs against HIF1A-AS2 provides a new direction for the treatment of BC.

Keywords: breast cancer, oncogenesis, HIF1A-AS2, miR-548c-3p, HIF-1α/VEGF, MCF-7


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