Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors
Abstract Cancer cells acquire the ability to reprogram their phenotype in response to targeted therapies, yet the transition from dormancy to proliferation in drug-resistant cancers remains poorly understood. In prostate cancer, we utilized high-plasticity mouse models and enzalutamide-resistant (EN...
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2024-12-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-024-03025-y |
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| author | Wenbin Chen Yiyou Mao YiYuan Zhan Wenfeng Li Jun Wu Xiangming Mao Bin Xu Fangpeng Shu |
| author_facet | Wenbin Chen Yiyou Mao YiYuan Zhan Wenfeng Li Jun Wu Xiangming Mao Bin Xu Fangpeng Shu |
| author_sort | Wenbin Chen |
| collection | DOAJ |
| description | Abstract Cancer cells acquire the ability to reprogram their phenotype in response to targeted therapies, yet the transition from dormancy to proliferation in drug-resistant cancers remains poorly understood. In prostate cancer, we utilized high-plasticity mouse models and enzalutamide-resistant (ENZ-R) cellular models to elucidate NR2F1 as a key factor in lineage transition and ENZ resistance. Depletion of NR2F1 drives ENZ-R cells into a relative dormancy state, characterized by reduced proliferation and heightened drug resistance, while NR2F1 overexpression yields contrasting outcomes. Transcriptional sequencing analysis of NR2F1-silenced prostate cancer cells and tissues from the Cancer Genome Atlas-prostate cancer and SU2C cohorts indicated exosomes as the most enriched cell component, with pathways implicated in steroid hormone biosynthesis and drug metabolism. Moreover, NR2F1-AS1 forms a complex with SRSF1 to upregulate NR2F1 expression, facilitating its binding with ESR1 to sustain hormonal receptor expression and enhance proliferation in ENZ-R cells. Furthermore, HnRNPA2B1 interacts with NR2F1 and NR2F1-AS1, assisting their packaging into exosomes, wherein exosomal NR2F1 and NR2F1-AS1 promote the proliferation of dormant ENZ-R cells. Our works offer novel insights into the reawaking of dormant drug-resistant cancer cells governed by NR2F1 upregulation triggered by exosome-derived NR2F1-AS1 and NR2F1, suggesting therapeutic potential for phenotype reversal. Graphical Abstract |
| format | Article |
| id | doaj-art-125ec5381ec34abd8915e4be01e46ee5 |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-125ec5381ec34abd8915e4be01e46ee52024-12-22T12:45:44ZengBMCJournal of Nanobiotechnology1477-31552024-12-0122111810.1186/s12951-024-03025-yExosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptorsWenbin Chen0Yiyou Mao1YiYuan Zhan2Wenfeng Li3Jun Wu4Xiangming Mao5Bin Xu6Fangpeng Shu7Department of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, Zhujiang Hospital, Southern Medical UniversityDepartment of Urology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Guangzhou Women and Children’s Medical Center, National Children’s Medical Center for South Central Region, Guangzhou Medical UniversityAbstract Cancer cells acquire the ability to reprogram their phenotype in response to targeted therapies, yet the transition from dormancy to proliferation in drug-resistant cancers remains poorly understood. In prostate cancer, we utilized high-plasticity mouse models and enzalutamide-resistant (ENZ-R) cellular models to elucidate NR2F1 as a key factor in lineage transition and ENZ resistance. Depletion of NR2F1 drives ENZ-R cells into a relative dormancy state, characterized by reduced proliferation and heightened drug resistance, while NR2F1 overexpression yields contrasting outcomes. Transcriptional sequencing analysis of NR2F1-silenced prostate cancer cells and tissues from the Cancer Genome Atlas-prostate cancer and SU2C cohorts indicated exosomes as the most enriched cell component, with pathways implicated in steroid hormone biosynthesis and drug metabolism. Moreover, NR2F1-AS1 forms a complex with SRSF1 to upregulate NR2F1 expression, facilitating its binding with ESR1 to sustain hormonal receptor expression and enhance proliferation in ENZ-R cells. Furthermore, HnRNPA2B1 interacts with NR2F1 and NR2F1-AS1, assisting their packaging into exosomes, wherein exosomal NR2F1 and NR2F1-AS1 promote the proliferation of dormant ENZ-R cells. Our works offer novel insights into the reawaking of dormant drug-resistant cancer cells governed by NR2F1 upregulation triggered by exosome-derived NR2F1-AS1 and NR2F1, suggesting therapeutic potential for phenotype reversal. Graphical Abstracthttps://doi.org/10.1186/s12951-024-03025-yProstate cancerNR2F1ExosomesPhenotypic transitionTreatment-resistant |
| spellingShingle | Wenbin Chen Yiyou Mao YiYuan Zhan Wenfeng Li Jun Wu Xiangming Mao Bin Xu Fangpeng Shu Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors Journal of Nanobiotechnology Prostate cancer NR2F1 Exosomes Phenotypic transition Treatment-resistant |
| title | Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors |
| title_full | Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors |
| title_fullStr | Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors |
| title_full_unstemmed | Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors |
| title_short | Exosome-delivered NR2F1-AS1 and NR2F1 drive phenotypic transition from dormancy to proliferation in treatment-resistant prostate cancer via stabilizing hormonal receptors |
| title_sort | exosome delivered nr2f1 as1 and nr2f1 drive phenotypic transition from dormancy to proliferation in treatment resistant prostate cancer via stabilizing hormonal receptors |
| topic | Prostate cancer NR2F1 Exosomes Phenotypic transition Treatment-resistant |
| url | https://doi.org/10.1186/s12951-024-03025-y |
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