RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotype
Abstract Background Triple-negative breast cancer (TNBC) is one of the breast cancer subtypes with a poor prognosis, and the current main treatment modalities include surgical resection and adjuvant chemotherapy. However, the development of drug resistance in tumor cells to chemotherapeutic agents p...
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2025-08-01
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| Online Access: | https://doi.org/10.1186/s41065-025-00534-0 |
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| author | Jinkun Fu Chao Wei Yijian Chen Xiaoming He Kun Zhang |
| author_facet | Jinkun Fu Chao Wei Yijian Chen Xiaoming He Kun Zhang |
| author_sort | Jinkun Fu |
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| description | Abstract Background Triple-negative breast cancer (TNBC) is one of the breast cancer subtypes with a poor prognosis, and the current main treatment modalities include surgical resection and adjuvant chemotherapy. However, the development of drug resistance in tumor cells to chemotherapeutic agents poses great challenges to anticancer treatment. Methods Bioinformatics analysis was used to screen the up-regulated genes in paclitaxel (PTX)-resistant TNBC cells. Cell viability was measured by a CCK-8 kit. TNFSF9 (Tumor necrosis factor receptor superfamily member 9) protein level was detected by Western blot (WB) assay. PTX-resistant TNBC cell lines (MDA-MB-231/PTX, MDA-MB-468/PTX) were constructed and their drug resistance was shown by IC50. The EdU, flow cytometry, Transwell, and other commercial kits were applied to detect the proliferation, apoptosis, migration, invasion, macrophage M2 polarization, and glycolysis of PTX-resistant TNBC cells. RBM15 (RNA binding motif protein 15) levels were measured by RT-qPCR and WB assays. The RIP, MeRIP, and actinomycin D assays were used to analyze the interaction between TNFSF9 and RBM15. The effect of RBM15/TNFSF9 on PTX sensitivity in vivo was verified by xenograft tumor experiments. Results TNFSF9 was highly expressed in PTX-resistant TNBC cells. Silencing of TNFSF9 enhanced the sensitivity to PTX. Silencing TNFSF9 induced polarization of macrophages from M2 to M1 phenotype and the release of IL-1β and TNF-α, but decreased the levels of IL-10 and TGF-β. RBM15 targeted the N6-adenylate methylation (m6A) modification of TNFSF9, and overexpression of TNFSF9 could reverse the tumor-suppressing effect of silencing RBM15 on PTX-resistant TNBC cells in vitro and transplanted tumors in vivo. Samples from PTX-sensitive and PTX-resistant TNBC patients proved that RBM15 regulated TNFSF9’s high expression in PTX-resistant TNBC tissues. Conclusion This study demonstrated that RBM15 enhanced PTX resistance in TNBC by promoting m6A methylation in TNFSF9 and inducing M2 polarization of tumor-associated macrophages. Graphical abstract RBM15/TNFSF9 enhances the resistance of TNBC cells to PTX. RBM15 induced m6A modification of TNFSF9 to stabilize its expression by binding to it. Subsequently, high levels of TNFSF9 enhanced the proliferation, migration, invasion, and glycolytic pathways of PTX-resistant TNBC cells, but blocked the occurrence of apoptosis. At the same time, the M2 phenotype polarization of macrophages was also promoted. All these effects enhanced the resistance of TNBC cells to PTX |
| format | Article |
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| institution | Kabale University |
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| language | English |
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| spelling | doaj-art-d08b4bcf335249859c6699c79959ffd32025-08-24T11:33:27ZengBMCHereditas1601-52232025-08-01162111610.1186/s41065-025-00534-0RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotypeJinkun Fu0Chao Wei1Yijian Chen2Xiaoming He3Kun Zhang4Department of General Surgery, Xianyang Hospital of Yan’an UniversityDepartment of General Surgery, Xianyang Hospital of Yan’an UniversityDepartment of General Surgery, Xianyang Hospital of Yan’an UniversityDepartment of General Surgery, Xianyang Hospital of Yan’an UniversityDepartment of Tumor and Thoracic Surgery, Xianyang Hospital of Yan’an UniversityAbstract Background Triple-negative breast cancer (TNBC) is one of the breast cancer subtypes with a poor prognosis, and the current main treatment modalities include surgical resection and adjuvant chemotherapy. However, the development of drug resistance in tumor cells to chemotherapeutic agents poses great challenges to anticancer treatment. Methods Bioinformatics analysis was used to screen the up-regulated genes in paclitaxel (PTX)-resistant TNBC cells. Cell viability was measured by a CCK-8 kit. TNFSF9 (Tumor necrosis factor receptor superfamily member 9) protein level was detected by Western blot (WB) assay. PTX-resistant TNBC cell lines (MDA-MB-231/PTX, MDA-MB-468/PTX) were constructed and their drug resistance was shown by IC50. The EdU, flow cytometry, Transwell, and other commercial kits were applied to detect the proliferation, apoptosis, migration, invasion, macrophage M2 polarization, and glycolysis of PTX-resistant TNBC cells. RBM15 (RNA binding motif protein 15) levels were measured by RT-qPCR and WB assays. The RIP, MeRIP, and actinomycin D assays were used to analyze the interaction between TNFSF9 and RBM15. The effect of RBM15/TNFSF9 on PTX sensitivity in vivo was verified by xenograft tumor experiments. Results TNFSF9 was highly expressed in PTX-resistant TNBC cells. Silencing of TNFSF9 enhanced the sensitivity to PTX. Silencing TNFSF9 induced polarization of macrophages from M2 to M1 phenotype and the release of IL-1β and TNF-α, but decreased the levels of IL-10 and TGF-β. RBM15 targeted the N6-adenylate methylation (m6A) modification of TNFSF9, and overexpression of TNFSF9 could reverse the tumor-suppressing effect of silencing RBM15 on PTX-resistant TNBC cells in vitro and transplanted tumors in vivo. Samples from PTX-sensitive and PTX-resistant TNBC patients proved that RBM15 regulated TNFSF9’s high expression in PTX-resistant TNBC tissues. Conclusion This study demonstrated that RBM15 enhanced PTX resistance in TNBC by promoting m6A methylation in TNFSF9 and inducing M2 polarization of tumor-associated macrophages. Graphical abstract RBM15/TNFSF9 enhances the resistance of TNBC cells to PTX. RBM15 induced m6A modification of TNFSF9 to stabilize its expression by binding to it. Subsequently, high levels of TNFSF9 enhanced the proliferation, migration, invasion, and glycolytic pathways of PTX-resistant TNBC cells, but blocked the occurrence of apoptosis. At the same time, the M2 phenotype polarization of macrophages was also promoted. All these effects enhanced the resistance of TNBC cells to PTXhttps://doi.org/10.1186/s41065-025-00534-0Triple-negative breast cancerPTX-resistantTNFSF9RBM15M2 polarization |
| spellingShingle | Jinkun Fu Chao Wei Yijian Chen Xiaoming He Kun Zhang RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotype Hereditas Triple-negative breast cancer PTX-resistant TNFSF9 RBM15 M2 polarization |
| title | RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotype |
| title_full | RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotype |
| title_fullStr | RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotype |
| title_full_unstemmed | RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotype |
| title_short | RBM15 enhances paclitaxel resistance in triple-negative breast cancer by targeting m6A methylation of TNFSF9 and inducing polarization of tumor-associated macrophages to M2 phenotype |
| title_sort | rbm15 enhances paclitaxel resistance in triple negative breast cancer by targeting m6a methylation of tnfsf9 and inducing polarization of tumor associated macrophages to m2 phenotype |
| topic | Triple-negative breast cancer PTX-resistant TNFSF9 RBM15 M2 polarization |
| url | https://doi.org/10.1186/s41065-025-00534-0 |
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