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CircASH2L facilitates tumor-like biologic behaviours and inflammation of fibroblast-like synoviocytes via miR-129-5p/HIPK2 axis in rheumatoid arthritis

Li, Xia, Qu, Meiting, Zhang, Jie, Chen, Kuanyin, Ma, Xianghui·2021·Journal of Orthopaedic Surgery and Research
DOI 10.1186/s13018-021-02432-3PMC PMC8106127
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Abstract

Background: Previous study showed that circular RNA Absent-Small-Homeotic-2--Like protein (circASH2L) was higher in rheumatoid arthritis (RA) patients. However, the roles and mechanisms of circASH2L in RA progression remain unclear. Methods: Levels analysis was conducted using western blot and qRT-PCR. The proliferation, apoptosis, cell cycle progression, migration, invasiveness, and inflammation of RA fibroblast-like synoviocytes (RA-FLSs) were determined via MTT, flow cytometry, western blot, transwell, and ELISA assays. Results: CircASH2L knockdown in RA-FLSs suppressed cell proliferative, migratory, and invasive capacities, triggered cell cycle arrest, promoted apoptosis, and inhibited inflammation. Mechanistically, circASH2L targeted miR-129-5p, and repression of miR-129-5p abolished the functions of circASH2L silencing on the growth, motility, and inflammation of RA-FLSs. Besides, miR-129-5p was found to directly target HIPK2, and suppressed the tumor-like biologic behaviors and inflammation of RA-FLSs via regulating HIPK2. Importantly, we proved that circASH2L could modulate HIPK2 expression via miR-129-5p. Conclusion: CircASH2L promoted RA-FLS growth, motility, and inflammation through miR-129-5p/HIPK2 axis.

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Figures

Fig. 1 CircASH2L expression in RA. a Schematic illustration demonstrates the formation of circASH2L via the circularization of exons 11 and 12 in ASH2L. b, c Detection of circASH2L expression in synovial tissues with RA and non-RA, as well as in RA-FLSs and N-FLSs with qRT-PCR. d Detection of circASH2L and linear ASH2L mRNA expression in RA-FLSs after RNase R treatment using qRT-PCR analysis. *P<0.05
Fig. 1 CircASH2L expression in RA. a Schematic illustration demonstrates the formation of circASH2L via the circularization of exons 11 and 12 in ASH2L. b, c Detection of circASH2L expression in synovial tissues with RA and non-RA, as well as in RA-FLSs and N-FLSs with qRT-PCR. d Detection of circASH2L and linear ASH2L mRNA expression in RA-FLSs after RNase R treatment using qRT-PCR analysis. *P<0.05CC BY · PubMed Central
Fig. 2 Effects of circASH2L on the tumor-like biologic behaviors of RA-FLSs. a-i si-circASH2L or si-NC was transfected into RA-FLSs, respectively. a Measurement of circASH2L expression in RA-FLSs with qRT-PCR. b, c Cell proliferation analysis with MTT assay and Edu assay. d Flow cytometry for cell apoptosis. e Detection of apoptosis-related protein using western blot. f Flow cytometry of cell cycle analysis. g, h Cell migration and invasion analysis with transwell assay. i Detection of inflammatory cytokines expression using ELISA. *P<0.05
Fig. 2 Effects of circASH2L on the tumor-like biologic behaviors of RA-FLSs. a-i si-circASH2L or si-NC was transfected into RA-FLSs, respectively. a Measurement of circASH2L expression in RA-FLSs with qRT-PCR. b, c Cell proliferation analysis with MTT assay and Edu assay. d Flow cytometry for cell apoptosis. e Detection of apoptosis-related protein using western blot. f Flow cytometry of cell cycle analysis. g, h Cell migration and invasion analysis with transwell assay. i Detection of inflammatory cytokines expression using ELISA. *P<0.05CC BY · PubMed Central
Fig. 3 CircASH2L directly bind to miR-129-5p in RA-FLSs. a Binding sites between miR-129-5p and circASH2L. b Interaction analysis between miR-129-5p and circASH2L using the dual-luciferase reporter assay. c, d MiR-129-5p expression in synovial tissues with RA and non-RA, as well as in RA-FLSs and N-FLSs was examined by qRT-PCR. e qRT-PCR analysis of miR-129-5p expression in circASH2L-decreased RA-FLSs. *P<0.05
Fig. 3 CircASH2L directly bind to miR-129-5p in RA-FLSs. a Binding sites between miR-129-5p and circASH2L. b Interaction analysis between miR-129-5p and circASH2L using the dual-luciferase reporter assay. c, d MiR-129-5p expression in synovial tissues with RA and non-RA, as well as in RA-FLSs and N-FLSs was examined by qRT-PCR. e qRT-PCR analysis of miR-129-5p expression in circASH2L-decreased RA-FLSs. *P<0.05CC BY · PubMed Central
Fig. 4 Knockdown of circASH2L suppresses the tumor-like biologic behaviors of RA-FLSs through miR-129-5p. a-i RA-FLSs were co-transfected with si-circASH2L and/or anti-miR-129-5p. a qRT-PCR analysis of miR-129-5p expression in RA-FLSs. b, c Cell proliferation analysis using MTT assay and Edu assay. d Flow cytometry of cell apoptosis analysis. e Detection of apoptosis-related protein expression using western blot. f Flow cytometry of cell cycle analysis. g, h The migratory and invasive activities analysis of cells using transwell assay. i) The measurement of inflammatory cytokines levels using ELISA. *P<0.05
Fig. 4 Knockdown of circASH2L suppresses the tumor-like biologic behaviors of RA-FLSs through miR-129-5p. a-i RA-FLSs were co-transfected with si-circASH2L and/or anti-miR-129-5p. a qRT-PCR analysis of miR-129-5p expression in RA-FLSs. b, c Cell proliferation analysis using MTT assay and Edu assay. d Flow cytometry of cell apoptosis analysis. e Detection of apoptosis-related protein expression using western blot. f Flow cytometry of cell cycle analysis. g, h The migratory and invasive activities analysis of cells using transwell assay. i) The measurement of inflammatory cytokines levels using ELISA. *P<0.05CC BY · PubMed Central
Fig. 5 CircASH2L indirectly regulates HIPK2 via miR-129-5p in RA-FLSs. a Binding sites of miR-129-5p on HIPK2 3′UTR. b Interaction analysis between miR-129-5p and HIPK2 using the dual-luciferase reporter assay. c-f HIPK2 expression level in synovial tissues with RA and non-RA, as well as in RA-FLSs and N-FLSs was determined. g MiR-129-5p expression analysis using qRT-PCR in RA-FLSs transfected with miR-NC or miR-129-5p. h, i HIPK2 expression analysis in miR-129-5p-increased RA-FLSs with qRT-PCR and western blot. j, k RA-FLSs were co-transfected with si-circASH2L and/or anti-miR-129-5p and HIPK2 level was examined using qRT-PCR and western blot. *P<0.05
Fig. 5 CircASH2L indirectly regulates HIPK2 via miR-129-5p in RA-FLSs. a Binding sites of miR-129-5p on HIPK2 3′UTR. b Interaction analysis between miR-129-5p and HIPK2 using the dual-luciferase reporter assay. c-f HIPK2 expression level in synovial tissues with RA and non-RA, as well as in RA-FLSs and N-FLSs was determined. g MiR-129-5p expression analysis using qRT-PCR in RA-FLSs transfected with miR-NC or miR-129-5p. h, i HIPK2 expression analysis in miR-129-5p-increased RA-FLSs with qRT-PCR and western blot. j, k RA-FLSs were co-transfected with si-circASH2L and/or anti-miR-129-5p and HIPK2 level was examined using qRT-PCR and western blot. *P<0.05CC BY · PubMed Central
Fig. 6 MiR-129-5p impairs RA-FLS tumor-like biologic behaviors through HIPK2. The miR-129-5p and/or HIPK2 were co-transfected into RA-FLSs. After transfection, a western blot analysis of HIPK2 expression using western blot; b, c MTT assay of cell proliferation and Edu assay; d flow cytometry of cell apoptosis detection; e western blot analysis of apoptosis-related protein expression in cells; f flow cytometry for cell cycle analysis; g, h cell migratory and invasive abilities detection using transwell assay; i the measurement of inflammatory cytokines levels using ELISA. *P<0.05
Fig. 6 MiR-129-5p impairs RA-FLS tumor-like biologic behaviors through HIPK2. The miR-129-5p and/or HIPK2 were co-transfected into RA-FLSs. After transfection, a western blot analysis of HIPK2 expression using western blot; b, c MTT assay of cell proliferation and Edu assay; d flow cytometry of cell apoptosis detection; e western blot analysis of apoptosis-related protein expression in cells; f flow cytometry for cell cycle analysis; g, h cell migratory and invasive abilities detection using transwell assay; i the measurement of inflammatory cytokines levels using ELISA. *P<0.05CC BY · PubMed Central

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Metadata

Authors
Li, X., Qu, M., Zhang, J., Chen, K., & Ma, X.
Venue
Journal of Orthopaedic Surgery and Research
Publisher
Springer Science and Business Media LLC
Published
2021-05-08
Volume
16
Issue
1
ISSN
1749-799X
DOI
10.1186/s13018-021-02432-3
PMC
PMC8106127
Cited by
18
References
1
Language
en
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