The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis
Abstract Background Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods We have developed a mouse model simulating clinical ster...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-023-00896-5 |
| _version_ | 1828069515254038528 |
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| author | Seulgi Jeon Hee Jin Jin-Mo Kim Youmin Hur Eun Joo Song Yoon-Jin Lee Younghwa Na Jaeho Cho Yun-Sil Lee |
| author_facet | Seulgi Jeon Hee Jin Jin-Mo Kim Youmin Hur Eun Joo Song Yoon-Jin Lee Younghwa Na Jaeho Cho Yun-Sil Lee |
| author_sort | Seulgi Jeon |
| collection | DOAJ |
| description | Abstract Background Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. Results HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Conclusions Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF. |
| first_indexed | 2024-04-11T00:21:11Z |
| format | Article |
| id | doaj.art-d0a375e845924f3cbfe10b963f6260a5 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-04-11T00:21:11Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-d0a375e845924f3cbfe10b963f6260a52023-01-08T12:17:38ZengBMCJournal of Biomedical Science1423-01272023-01-0130111510.1186/s12929-023-00896-5The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosisSeulgi Jeon0Hee Jin1Jin-Mo Kim2Youmin Hur3Eun Joo Song4Yoon-Jin Lee5Younghwa Na6Jaeho Cho7Yun-Sil Lee8Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityGraduate School of Pharmaceutical Sciences, Ewha Womans UniversityDepartment of Radiation Oncology, Yonsei University Health SystemGraduate School of Pharmaceutical Sciences, Ewha Womans UniversityGraduate School of Pharmaceutical Sciences, Ewha Womans UniversityKorea Institute of Radiological and Medical ScienceCollege of Pharmacy, CHA UniversityDepartment of Radiation Oncology, Yonsei University Health SystemGraduate School of Pharmaceutical Sciences, Ewha Womans UniversityAbstract Background Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. Results HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Conclusions Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.https://doi.org/10.1186/s12929-023-00896-5HSP27PhosphorylationmiRNAPulmonary fibrosisSmurf2Protein degradation |
| spellingShingle | Seulgi Jeon Hee Jin Jin-Mo Kim Youmin Hur Eun Joo Song Yoon-Jin Lee Younghwa Na Jaeho Cho Yun-Sil Lee The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis Journal of Biomedical Science HSP27 Phosphorylation miRNA Pulmonary fibrosis Smurf2 Protein degradation |
| title | The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis |
| title_full | The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis |
| title_fullStr | The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis |
| title_full_unstemmed | The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis |
| title_short | The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis |
| title_sort | mir 15b smurf2 hsp27 axis promotes pulmonary fibrosis |
| topic | HSP27 Phosphorylation miRNA Pulmonary fibrosis Smurf2 Protein degradation |
| url | https://doi.org/10.1186/s12929-023-00896-5 |
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