The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development
Background Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/5/e006230.full |
| _version_ | 1797822176912474112 |
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| author | Baoen Shan Cong Zhang Guogui Sun Hongtao Zhang Xiaoya Li Sisi Wei Suli Dai Huixia Wang Lianmei Zhao |
| author_facet | Baoen Shan Cong Zhang Guogui Sun Hongtao Zhang Xiaoya Li Sisi Wei Suli Dai Huixia Wang Lianmei Zhao |
| author_sort | Baoen Shan |
| collection | DOAJ |
| description | Background Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for tumors. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, yet the underlying mechanism on how lncRNAs manipulate the polarization states of TAMs is still unclear and remains to be further investigated.Methods Microarray analyses were employed to characterize the lncRNA profile involved in THP-1-induced M0, M1 and M2-like macrophage. Among those differentially expressed lncRNAs, NR_109 was further studied, for its function in M2-like macrophage polarization and the effects of the condition medium or macrophages mediated by NR_109 on tumor proliferation, metastasis and TME remodeling both in vitro and in vivo. Moreover, we revealed how NR_109 interacted with far upstream element-binding protein 1 (FUBP1) to regulate the protein stability through hindering ubiquitination modification by competitively binding with JVT-1. Finally, we examined sections of tumor patients to probe the correlation among the expression of NR_109 and related proteins, showing the clinical significance of NR_109.Results We found that lncRNA NR_109 was highly expressed in M2-like macrophages. Knockdown NR_109 impeded IL-4 induced M2-like macrophage polarization and significantly reduced the activity of M2-like macrophages to support the proliferation and metastasis of tumor cells in vitro and in vivo. Mechanistically, NR_109 competed with JVT-1 to bind FUBP1 at its C-terminus domain, impeded the ubiquitin-mediated degradation of FUBP1, activated c-Myc transcription and thus promoted M2-like macrophages polarization. Meanwhile, as a transcription factor, c-Myc could bind to the promoter of NR_109 and enhance the transcription of NR_109. Clinically, high NR_109 expression was found in CD163+ TAMs from tumor tissues and was positively correlated with poor clinical stages of patients with gastric cancer and breast cancer.Conclusions Our work revealed for the first time that NR_109 exerted a crucial role in regulating the phenotype-remodeling and function of M2-like macrophages via a NR_109/FUBP1/c-Myc positive feedback loop. Thus, NR_109 has great translational potentials in the diagnosis, prognosis and immunotherapy of cancer. |
| first_indexed | 2024-03-13T10:04:06Z |
| format | Article |
| id | doaj.art-2de85bce8d3e4dd988a530b2d1ad51f8 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-13T10:04:06Z |
| publishDate | 2023-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-2de85bce8d3e4dd988a530b2d1ad51f82023-05-22T20:00:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-05-0111510.1136/jitc-2022-006230The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer developmentBaoen Shan0Cong Zhang1Guogui Sun2Hongtao Zhang3Xiaoya Li4Sisi Wei5Suli Dai6Huixia Wang7Lianmei Zhao81Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People`s Republic of ChinaState Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Haidian District, ChinaprofessorDepartment of Radiology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China1 Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, ChinaResearch Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, ChinaResearch Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, ChinaResearch Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, ChinaResearch Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, ChinaBackground Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for tumors. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, yet the underlying mechanism on how lncRNAs manipulate the polarization states of TAMs is still unclear and remains to be further investigated.Methods Microarray analyses were employed to characterize the lncRNA profile involved in THP-1-induced M0, M1 and M2-like macrophage. Among those differentially expressed lncRNAs, NR_109 was further studied, for its function in M2-like macrophage polarization and the effects of the condition medium or macrophages mediated by NR_109 on tumor proliferation, metastasis and TME remodeling both in vitro and in vivo. Moreover, we revealed how NR_109 interacted with far upstream element-binding protein 1 (FUBP1) to regulate the protein stability through hindering ubiquitination modification by competitively binding with JVT-1. Finally, we examined sections of tumor patients to probe the correlation among the expression of NR_109 and related proteins, showing the clinical significance of NR_109.Results We found that lncRNA NR_109 was highly expressed in M2-like macrophages. Knockdown NR_109 impeded IL-4 induced M2-like macrophage polarization and significantly reduced the activity of M2-like macrophages to support the proliferation and metastasis of tumor cells in vitro and in vivo. Mechanistically, NR_109 competed with JVT-1 to bind FUBP1 at its C-terminus domain, impeded the ubiquitin-mediated degradation of FUBP1, activated c-Myc transcription and thus promoted M2-like macrophages polarization. Meanwhile, as a transcription factor, c-Myc could bind to the promoter of NR_109 and enhance the transcription of NR_109. Clinically, high NR_109 expression was found in CD163+ TAMs from tumor tissues and was positively correlated with poor clinical stages of patients with gastric cancer and breast cancer.Conclusions Our work revealed for the first time that NR_109 exerted a crucial role in regulating the phenotype-remodeling and function of M2-like macrophages via a NR_109/FUBP1/c-Myc positive feedback loop. Thus, NR_109 has great translational potentials in the diagnosis, prognosis and immunotherapy of cancer.https://jitc.bmj.com/content/11/5/e006230.full |
| spellingShingle | Baoen Shan Cong Zhang Guogui Sun Hongtao Zhang Xiaoya Li Sisi Wei Suli Dai Huixia Wang Lianmei Zhao The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development Journal for ImmunoTherapy of Cancer |
| title | The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development |
| title_full | The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development |
| title_fullStr | The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development |
| title_full_unstemmed | The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development |
| title_short | The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development |
| title_sort | nr 109 fubp1 c myc axis regulates tam polarization and remodels the tumor microenvironment to promote cancer development |
| url | https://jitc.bmj.com/content/11/5/e006230.full |
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