TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum
Abstract Background Hypertrophy of ligamentum flavum (HLF) is the mainly cause of lumbar spinal stenosis (LSS), but the precise mechanism of HLF formation has not been fully elucidated. Emerging evidence indicates that transcription factor 7 (TCF7) is the key downstream functional molecule of Wnt/β-...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-10-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03677-0 |
| _version_ | 1828343084672352256 |
|---|---|
| author | Yang Duan Jianjun Li Sujun Qiu Songjia Ni Yanlin Cao |
| author_facet | Yang Duan Jianjun Li Sujun Qiu Songjia Ni Yanlin Cao |
| author_sort | Yang Duan |
| collection | DOAJ |
| description | Abstract Background Hypertrophy of ligamentum flavum (HLF) is the mainly cause of lumbar spinal stenosis (LSS), but the precise mechanism of HLF formation has not been fully elucidated. Emerging evidence indicates that transcription factor 7 (TCF7) is the key downstream functional molecule of Wnt/β-catenin signaling, which participated in regulating multiple biological processes. However, the role and underlying mechanism of TCF7 in HLF is still unclear. Methods We used mRNAs sequencing analysis of human LF and subsequent confirmation with RT-qPCR, western blot and immunohistochemistry to identified the TCF7 in HLF tissues and cells. Then effect of TCF7 on HLF progression was investigated both in vitro and in vivo. Mechanically, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments were used to validate the regulation of TCF7/SNAI2/miR-4306 feedback loop. Results Our results identified for first time that the TCF7 expression was obviously elevated in HLF tissues and cells compared with control, and also found that TCF7 expression had significant positive correlation with LF thickness and fibrosis score. Notably, TCF7 inhibition suppressed the hyper-proliferation and fibrosis phenotype of HLF cells in vitro and ameliorated progression of HLF in mice in vivo, whereas TCF7 overexpression promoted hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Our data further revealed that TCF7 interacted with SNAI2 promoter to transactivated the SNAI2 expression, thereby promoting hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Furthermore, miR-4036 negatively regulated by SNAI2 could negatively feedback regulate TCF7 expression by directly binding to TCF7 mRNA 3’-UTR, thus inhibiting the hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Conclusions Our study demonstrated that TCF7 inhibition could suppress HLF formation by modulating TCF7/SNAI2/miR-4306 feedback loop, which might be considered as a novel potential therapeutic target for HLF. |
| first_indexed | 2024-04-13T23:37:58Z |
| format | Article |
| id | doaj.art-52c4f0440164430cbf6b2ba7b9fed9e4 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-13T23:37:58Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-52c4f0440164430cbf6b2ba7b9fed9e42022-12-22T02:24:39ZengBMCJournal of Translational Medicine1479-58762022-10-0120111710.1186/s12967-022-03677-0TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavumYang Duan0Jianjun Li1Sujun Qiu2Songjia Ni3Yanlin Cao4Department of Spine Surgery, Zhujiang Hospital, Southern Medical UniversityDepartment of Spine Surgery, Zhujiang Hospital, Southern Medical UniversityDepartment of Spine Surgery, Zhujiang Hospital, Southern Medical UniversityDepartment of Orthopaedic Trauma, Zhujiang Hospital, Southern Medical UniversityDepartment of Spine Surgery, Zhujiang Hospital, Southern Medical UniversityAbstract Background Hypertrophy of ligamentum flavum (HLF) is the mainly cause of lumbar spinal stenosis (LSS), but the precise mechanism of HLF formation has not been fully elucidated. Emerging evidence indicates that transcription factor 7 (TCF7) is the key downstream functional molecule of Wnt/β-catenin signaling, which participated in regulating multiple biological processes. However, the role and underlying mechanism of TCF7 in HLF is still unclear. Methods We used mRNAs sequencing analysis of human LF and subsequent confirmation with RT-qPCR, western blot and immunohistochemistry to identified the TCF7 in HLF tissues and cells. Then effect of TCF7 on HLF progression was investigated both in vitro and in vivo. Mechanically, chromatin immunoprecipitation, dual-luciferase reporter assays, and rescue experiments were used to validate the regulation of TCF7/SNAI2/miR-4306 feedback loop. Results Our results identified for first time that the TCF7 expression was obviously elevated in HLF tissues and cells compared with control, and also found that TCF7 expression had significant positive correlation with LF thickness and fibrosis score. Notably, TCF7 inhibition suppressed the hyper-proliferation and fibrosis phenotype of HLF cells in vitro and ameliorated progression of HLF in mice in vivo, whereas TCF7 overexpression promoted hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Our data further revealed that TCF7 interacted with SNAI2 promoter to transactivated the SNAI2 expression, thereby promoting hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Furthermore, miR-4036 negatively regulated by SNAI2 could negatively feedback regulate TCF7 expression by directly binding to TCF7 mRNA 3’-UTR, thus inhibiting the hyper-proliferation and fibrosis phenotype of HLF cells in vitro. Conclusions Our study demonstrated that TCF7 inhibition could suppress HLF formation by modulating TCF7/SNAI2/miR-4306 feedback loop, which might be considered as a novel potential therapeutic target for HLF.https://doi.org/10.1186/s12967-022-03677-0Ligamentum flavum hypertrophyTCF7SNAI2miR-4306 |
| spellingShingle | Yang Duan Jianjun Li Sujun Qiu Songjia Ni Yanlin Cao TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum Journal of Translational Medicine Ligamentum flavum hypertrophy TCF7 SNAI2 miR-4306 |
| title | TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum |
| title_full | TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum |
| title_fullStr | TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum |
| title_full_unstemmed | TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum |
| title_short | TCF7/SNAI2/miR-4306 feedback loop promotes hypertrophy of ligamentum flavum |
| title_sort | tcf7 snai2 mir 4306 feedback loop promotes hypertrophy of ligamentum flavum |
| topic | Ligamentum flavum hypertrophy TCF7 SNAI2 miR-4306 |
| url | https://doi.org/10.1186/s12967-022-03677-0 |
| work_keys_str_mv | AT yangduan tcf7snai2mir4306feedbacklooppromoteshypertrophyofligamentumflavum AT jianjunli tcf7snai2mir4306feedbacklooppromoteshypertrophyofligamentumflavum AT sujunqiu tcf7snai2mir4306feedbacklooppromoteshypertrophyofligamentumflavum AT songjiani tcf7snai2mir4306feedbacklooppromoteshypertrophyofligamentumflavum AT yanlincao tcf7snai2mir4306feedbacklooppromoteshypertrophyofligamentumflavum |