Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization
Abstract Background This study aimed to investigate the role of Collagen triple helix repeat protein 1 (CTHRC1) in Wilms’ tumor (WT) progression and elucidate its molecular mechanism in promoting WT malignancy through regulation of M2-type tumor-associated macrophages (M2-TAMs) infiltration and pola...
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06752-4 |
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| author | Yingquan Zhuo Xiaoyun Feng Wenqi Zhang Jun Du Xu Sun Xi Luo Wei Wang Hua Jiang Huajian Gu |
| author_facet | Yingquan Zhuo Xiaoyun Feng Wenqi Zhang Jun Du Xu Sun Xi Luo Wei Wang Hua Jiang Huajian Gu |
| author_sort | Yingquan Zhuo |
| collection | DOAJ |
| description | Abstract Background This study aimed to investigate the role of Collagen triple helix repeat protein 1 (CTHRC1) in Wilms’ tumor (WT) progression and elucidate its molecular mechanism in promoting WT malignancy through regulation of M2-type tumor-associated macrophages (M2-TAMs) infiltration and polarization. Methods Bioinformatics analysis was conducted using public databases to examine CTHRC1 expression and immune cell infiltration in WT. Single-cell sequencing was employed to analyze expression patterns of CTHRC1 and M2-TAMs markers. CTHRC1 expression and M2-TAM infiltration were validated in WT tissues using RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence. In vitro and in vivo experiments were performed to investigate the biological functions of CTHRC1 in WT and its effects on M2-TAMs polarization. Transcriptome sequencing and bioinformatics analysis were used to explore potential signaling pathways. The TNFSF9-TNFRSF9 axis was further investigated through neutralizing antibody rescue experiments and co-localization analysis. The role of M2-TAMs in promoting WT progression via the PI3K/AKt pathway was examined using xenograft models and in vitro experiments. Results CTHRC1 and M2-TAMs were significantly overexpressed in WT tissues and positively correlated. CTHRC1 overexpression promoted WT cell proliferation, inhibited apoptosis, and induced M2-TAMs polarization both in vitro and in vivo. Transcriptome analysis revealed that CTHRC1 regulated M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. CTHRC1 overexpression upregulated TNFSF9: expression and secretion in tumor cells, promoting its binding to TNFRSF9 on M2-TAMs. Neutralizing TNFSF9 or knockdown of TNFRSF9 significantly attenuated CTHRC1-induced M2-TAM infiltration and polarization. M2-TAMs promoted WT progression by activating the PI3K/Akt pathway in tumor cells. Inhibition of PI3K/Akt signaling reversed M2-TAM-mediated WT progression. Conclusions CTHRC1 promotes WT progression by inducing M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. M2-TAMs, in turn, enhance WT malignancy by activating the PI3K/Akt pathway in tumor cells. These findings provide new potential biomarkers and therapeutic targets for WT diagnosis and treatment. |
| format | Article |
| id | doaj-art-df4c85dae01c42469bb3b85fecd0772e |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-df4c85dae01c42469bb3b85fecd0772e2025-08-20T04:02:55ZengBMCJournal of Translational Medicine1479-58762025-07-0123112410.1186/s12967-025-06752-4Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarizationYingquan Zhuo0Xiaoyun Feng1Wenqi Zhang2Jun Du3Xu Sun4Xi Luo5Wei Wang6Hua Jiang7Huajian Gu8Department of Pediatric Surgery, The Afliated Hospital of Guizhou Medical UniversityShizhen College, Guizhou University of Traditional Chinese MedicineDepartment of Anesthesiology, The Afliated Hospital of Guizhou Medical UniversityDepartment of Pediatric Surgery, The Afliated Hospital of Guizhou Medical UniversityDepartment of Pediatric Surgery, The Afliated Hospital of Guizhou Medical UniversityDepartment of Pediatric Surgery, The Afliated Hospital of Guizhou Medical UniversitySchool of Clinical Medicine, Guizhou Medical UniversityDepartment of Pediatric Surgery, The Afliated Hospital of Guizhou Medical UniversityDepartment of Pediatric Surgery, The Afliated Hospital of Guizhou Medical UniversityAbstract Background This study aimed to investigate the role of Collagen triple helix repeat protein 1 (CTHRC1) in Wilms’ tumor (WT) progression and elucidate its molecular mechanism in promoting WT malignancy through regulation of M2-type tumor-associated macrophages (M2-TAMs) infiltration and polarization. Methods Bioinformatics analysis was conducted using public databases to examine CTHRC1 expression and immune cell infiltration in WT. Single-cell sequencing was employed to analyze expression patterns of CTHRC1 and M2-TAMs markers. CTHRC1 expression and M2-TAM infiltration were validated in WT tissues using RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence. In vitro and in vivo experiments were performed to investigate the biological functions of CTHRC1 in WT and its effects on M2-TAMs polarization. Transcriptome sequencing and bioinformatics analysis were used to explore potential signaling pathways. The TNFSF9-TNFRSF9 axis was further investigated through neutralizing antibody rescue experiments and co-localization analysis. The role of M2-TAMs in promoting WT progression via the PI3K/AKt pathway was examined using xenograft models and in vitro experiments. Results CTHRC1 and M2-TAMs were significantly overexpressed in WT tissues and positively correlated. CTHRC1 overexpression promoted WT cell proliferation, inhibited apoptosis, and induced M2-TAMs polarization both in vitro and in vivo. Transcriptome analysis revealed that CTHRC1 regulated M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. CTHRC1 overexpression upregulated TNFSF9: expression and secretion in tumor cells, promoting its binding to TNFRSF9 on M2-TAMs. Neutralizing TNFSF9 or knockdown of TNFRSF9 significantly attenuated CTHRC1-induced M2-TAM infiltration and polarization. M2-TAMs promoted WT progression by activating the PI3K/Akt pathway in tumor cells. Inhibition of PI3K/Akt signaling reversed M2-TAM-mediated WT progression. Conclusions CTHRC1 promotes WT progression by inducing M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. M2-TAMs, in turn, enhance WT malignancy by activating the PI3K/Akt pathway in tumor cells. These findings provide new potential biomarkers and therapeutic targets for WT diagnosis and treatment.https://doi.org/10.1186/s12967-025-06752-4Wilms’ tumorCTHRC1M2-TAMsTNFSF9-TNFRSF9PI3K/Akt signaling pathway |
| spellingShingle | Yingquan Zhuo Xiaoyun Feng Wenqi Zhang Jun Du Xu Sun Xi Luo Wei Wang Hua Jiang Huajian Gu Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization Journal of Translational Medicine Wilms’ tumor CTHRC1 M2-TAMs TNFSF9-TNFRSF9 PI3K/Akt signaling pathway |
| title | Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization |
| title_full | Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization |
| title_fullStr | Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization |
| title_full_unstemmed | Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization |
| title_short | Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization |
| title_sort | mechanistic study of cthrc1 in promoting wilms tumor progression by regulating m2 type tumor associated macrophages polarization |
| topic | Wilms’ tumor CTHRC1 M2-TAMs TNFSF9-TNFRSF9 PI3K/Akt signaling pathway |
| url | https://doi.org/10.1186/s12967-025-06752-4 |
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