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Down-regulation of lncRNA CASC9 aggravates sepsis-induced acute lung injury by regulating miR-195-5p/PDK4 axis

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Abstract

Background

Long non-coding RNA (lncRNA) cancer susceptibility candidate 9 (CASC9) is reported to be linked to cancers. This research aims to explore the role and possible mechanism of CASC9 in lung injury induced by sepsis.

Methods

Lipopolysaccharide (LPS) induced human small airway epithelial cells (HSAECs) were established in vitro to mimic sepsis-induced lung injury. The effects of CASC9 and miR-195-5p on HSAECs viability were studied by CCK-8 assay. Interactions between CASC9 and miR-195-5p were determined by bioinformatics analysis, RT-PCR, dual luciferase reporter assay, and RNA immunoprecipitation assay. Pyruvate dehydrogenase kinase 4 (PDK4) and apoptosis-related molecules including Bcl2 and Bad were detected by western blot. Additionally, sepsis-induced lung injury model in rats was established by intraperitoneal injection of LPS in vivo to validate the demonstrations of in vitro studies.

Results

CASC9 was markedly down-regulated while miR-195-5p was significantly up-regulated in HSAECs treated by LPS and lung tissues of rats with sepsis. CASC9 interacted with miR-195-5p, and negatively regulated its expression level. Overexpression of CASC9 or transfection of miR-195-5p inhibitors significantly promoted the viability of HSAECs. The transfection of miR-195-5p mimics effected oppositely. For mechanism, miR-195-5p targeted the 3′UTR of pyruvate dehydrogenase kinase 4 (PDK4) gene and depressed the protein level, and PDK4 was regulated indirectly by CASC9. Restoration of CASC9 in the lung tissues of rats with sepsis ameliorated lung injury.

Conclusion

CASC9 protects lung epithelial cells from sepsis-induced injury via regulating miR-195-5p/PDK4 axis.

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Data availability statement

The data used to support the findings of this study are available from the corresponding author upon request.

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Authors and Affiliations

  1. Deparment of Education, DongE Hospital Affiliated to Shandong First Medical University, Liaocheng, 252200, Shandong, China

    Huai-rong Wang & Xiu-yan Guo

  2. Intensive Care Unit, DongE Hospital Affiliated to Shandong First Medical University, 275# Shuguang Street, Liaocheng, 252200, Shandong, China

    Xin-yan Liu & Xuan Song

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  1. Huai-rong Wang
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  2. Xiu-yan Guo
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  3. Xin-yan Liu
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  4. Xuan Song
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Contributions

Guarantor of integrity of the entire study: XS; Study concepts and design: XS; Experimental studies: HRW, XYG; Data analysis: HRW, XYG; Manuscript preparation: XS, YXL. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xuan Song.

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The authors declare that they have no competing interest.

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Responsible Editor: Artur Bauhofer.

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Wang, Hr., Guo, Xy., Liu, Xy. et al. Down-regulation of lncRNA CASC9 aggravates sepsis-induced acute lung injury by regulating miR-195-5p/PDK4 axis. Inflamm. Res. 69, 559–568 (2020). https://doi.org/10.1007/s00011-020-01316-2

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  • DOI: https://doi.org/10.1007/s00011-020-01316-2

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