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Silencing of circHIPK3 hampers platelet-derived growth factor-induced proliferation and migration in airway smooth muscle cells through the miR-375/MMP-16 axis

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Abstract

Emerging evidence has suggested a pivotal role of circular RNAs (circRNAs) in the progression of asthma. In this paper, we explored the mechanisms underlying the modulation of circRNA homeodomain interacting protein kinase 3 (circHIPK3, circ_0000284) in airway smooth muscle cell (AMSC) migration and proliferation induced by platelet-derived growth factor (PDGF). The stability of circHIPK3 was gauged by Ribonuclease R (RNase R) and Actinomycin D assays. Relative expression levels of circHIPK3, microRNA (miR)-375 and matrix metallopeptidase 16 (MMP-16) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, invasion, and apoptosis were evaluated by Cell Counting Kit-8 (CCK-8) assay, transwell assay, and flow cytometry, respectively. Cell migration was detected by wound-healing and transwell assays. Direct relationship between miR-375 and circHIPK3 or MMP-16 was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Our results indicated that PDGF induced the expression of circHIPK3 in human AMSCs (HAMSCs). CircHIPK3 silencing impeded proliferation, migration, invasion and promoted apoptosis of PDGF-treated HAMSCs. Mechanistically, circHIPK3 targeted miR-375 by directly binding to miR-375. MiR-375 was a downstream effector of circHIPK3 in controlling PDGF-induced proliferation, invasion and migration. MMP-16 was directly targeted and inhibited by miR-375, and circHIPK3 functioned as a post-transcriptional modulator of MMP-16 expression through miR-375. Moreover, miR-375-mediated inhibition of MMP-16 impacted HAMSC proliferation, invasion and migration induced by PDGF. Our findings identified the miR-375/MMP-16 axis as a novel mechanism for the modulation of circHIPK3 in PDGF-induced migration and proliferation in HASMCs.

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Data Availability

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Respiratory Medicine, The NO.2, Hospital of Baoding, No. 338 Dongfeng West Road, Jingxiu District, 071000, Baoding, China

    Yu Jiang, Xiaoqing Guo & Junhong Qin

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  1. Yu Jiang
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  2. Xiaoqing Guo
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  3. Junhong Qin
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Contributions

XG designed the study. YJ conducted the experiments and drafted the manuscript. JQ collected and analyzed the data, edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yu Jiang.

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The authors declare that they have no conflict of interest.

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The research was authorized by the Ethics Committee of the NO. 2 Hospital of Baoding and was carried out according to the guidelines of Declaration of Helsinki. Each participant signed a written informed consent before conducting this study.

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Jiang, Y., Guo, X. & Qin, J. Silencing of circHIPK3 hampers platelet-derived growth factor-induced proliferation and migration in airway smooth muscle cells through the miR-375/MMP-16 axis. Cytotechnology 73, 629–642 (2021). https://doi.org/10.1007/s10616-021-00483-2

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  • DOI: https://doi.org/10.1007/s10616-021-00483-2

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