Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination
Abstract Background Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and has a poor prognosis. Previous studies have indicated that Fibroblast Growth Factor 7 (FGF7) plays a vital role in the development and progression of breast cancer. However, the role and molecular mec...
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2025-08-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-025-02099-2 |
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| author | Bo Huang Yichao Zhang Zhanjun Chen Yuanyuan Yuan Jianshan Lin |
| author_facet | Bo Huang Yichao Zhang Zhanjun Chen Yuanyuan Yuan Jianshan Lin |
| author_sort | Bo Huang |
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| description | Abstract Background Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and has a poor prognosis. Previous studies have indicated that Fibroblast Growth Factor 7 (FGF7) plays a vital role in the development and progression of breast cancer. However, the role and molecular mechanisms of FGF7 in TNBC remain largely unclear under hypoxia. Methods FGF7 and Methyltransferase-like 14 (METTL14) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). FGF7, tripartite motif-containing protein 16 (TRIM16), METTL14, METTL3, YTHDF1, WTAP, FTO, CD63, CD81, and TSG101 protein levels were examined by western blot. Cell viability, proliferation, invasion, and migration were determined using MTT, EdU, transwell, and wound healing assays. Glucose consumption, lactate production, and ATP levels were assessed using relevant kits. After STRING database analysis, the interaction between TRIM16 and FGF7 was verified using a Co-immunoprecipitation (CoIP) assay. Interaction between METTL14 and TRIM16 was validated using methylated RNA immunoprecipitation (MeRIP), RIP, and dual-luciferase reporter assays. The biological role of hypoxia-induced exosomal METTL14 on breast cancer tumor growth was assessed using the xenograft tumor model in vivo. Results FGF7 was highly expressed in TNBC patients and cell lines. Moreover, FGF7 expression was increased in the hypoxia group compared with the normoxia group. Functionally, FGF7 knockdown suppressed hypoxia-induced TNBC cell proliferation, metastasis, and glycolysis. Mechanistically, TRIM16 triggered the ubiquitination of FGF7 and promoted its degradation. METTL14 enhanced TRIM16 mRNA stability and expression by m6A methylation. Hypoxia-induced exosomal METTL14 knockdown repressed tumor growth in vivo. Conclusion Hypoxia-induced exosomal METTL14 supports the proliferation, metastasis, and glycolysis of TNBC cells through regulating TRIM16-mediated FGF7 ubiquitination, providing a promising therapeutic target for TNBC treatment. |
| format | Article |
| id | doaj-art-dc431e4199d9457fbaa5a63e65e4bf21 |
| institution | Kabale University |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | Breast Cancer Research |
| spelling | doaj-art-dc431e4199d9457fbaa5a63e65e4bf212025-08-20T04:02:49ZengBMCBreast Cancer Research1465-542X2025-08-0127111710.1186/s13058-025-02099-2Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitinationBo Huang0Yichao Zhang1Zhanjun Chen2Yuanyuan Yuan3Jianshan Lin4Department of Thyroid and Breast Surgery, The Second Affiliated Hospital of Shenzhen UniversityDepartment of Thyroid and Breast Surgery, The Second Affiliated Hospital of Shenzhen UniversityDepartment of Thyroid and Breast Surgery, The Second Affiliated Hospital of Shenzhen UniversityDepartment of Thyroid and Breast Surgery, The Second Affiliated Hospital of Shenzhen UniversityDepartment of Thyroid and Breast Surgery, The Second Affiliated Hospital of Shenzhen UniversityAbstract Background Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and has a poor prognosis. Previous studies have indicated that Fibroblast Growth Factor 7 (FGF7) plays a vital role in the development and progression of breast cancer. However, the role and molecular mechanisms of FGF7 in TNBC remain largely unclear under hypoxia. Methods FGF7 and Methyltransferase-like 14 (METTL14) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). FGF7, tripartite motif-containing protein 16 (TRIM16), METTL14, METTL3, YTHDF1, WTAP, FTO, CD63, CD81, and TSG101 protein levels were examined by western blot. Cell viability, proliferation, invasion, and migration were determined using MTT, EdU, transwell, and wound healing assays. Glucose consumption, lactate production, and ATP levels were assessed using relevant kits. After STRING database analysis, the interaction between TRIM16 and FGF7 was verified using a Co-immunoprecipitation (CoIP) assay. Interaction between METTL14 and TRIM16 was validated using methylated RNA immunoprecipitation (MeRIP), RIP, and dual-luciferase reporter assays. The biological role of hypoxia-induced exosomal METTL14 on breast cancer tumor growth was assessed using the xenograft tumor model in vivo. Results FGF7 was highly expressed in TNBC patients and cell lines. Moreover, FGF7 expression was increased in the hypoxia group compared with the normoxia group. Functionally, FGF7 knockdown suppressed hypoxia-induced TNBC cell proliferation, metastasis, and glycolysis. Mechanistically, TRIM16 triggered the ubiquitination of FGF7 and promoted its degradation. METTL14 enhanced TRIM16 mRNA stability and expression by m6A methylation. Hypoxia-induced exosomal METTL14 knockdown repressed tumor growth in vivo. Conclusion Hypoxia-induced exosomal METTL14 supports the proliferation, metastasis, and glycolysis of TNBC cells through regulating TRIM16-mediated FGF7 ubiquitination, providing a promising therapeutic target for TNBC treatment.https://doi.org/10.1186/s13058-025-02099-2HypoxiaTNBCFGF7TRIM16METTL14Proliferation |
| spellingShingle | Bo Huang Yichao Zhang Zhanjun Chen Yuanyuan Yuan Jianshan Lin Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination Breast Cancer Research Hypoxia TNBC FGF7 TRIM16 METTL14 Proliferation |
| title | Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination |
| title_full | Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination |
| title_fullStr | Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination |
| title_full_unstemmed | Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination |
| title_short | Exosome-delivered METTL14 drives hypoxia-induced proliferation, metastasis, and glycolysis of breast cancer cells through regulating TRIM16-mediated FGF7 ubiquitination |
| title_sort | exosome delivered mettl14 drives hypoxia induced proliferation metastasis and glycolysis of breast cancer cells through regulating trim16 mediated fgf7 ubiquitination |
| topic | Hypoxia TNBC FGF7 TRIM16 METTL14 Proliferation |
| url | https://doi.org/10.1186/s13058-025-02099-2 |
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