Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1
Abstract Background Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Ne...
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BMC
2025-05-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-025-03801-2 |
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| author | Kai Wang Xihao Shen Jiyue Wu Qing Bi Zihao Gao Zejia Sun Wei Wang |
| author_facet | Kai Wang Xihao Shen Jiyue Wu Qing Bi Zihao Gao Zejia Sun Wei Wang |
| author_sort | Kai Wang |
| collection | DOAJ |
| description | Abstract Background Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Neuropilin-1 (NRP1), a key mediator in fibrotic signaling and cancer biology, has been implicated in these processes. However, the genetic correlation between fibrogenesis and ccRCC remains largely unexplored, necessitating a focused analysis of fibrogenesis-related genes (FRGs) to identify novel prognostic markers and therapeutic strategies. Methods This study utilized an integrative bioinformatics framework to identify prognosis-associated fibrogenesis-related genes (pFRGs) and applied non-negative matrix factorization (NMF) to stratify ccRCC patients based on fibrotic signatures. A machine learning-derived prognostic model was developed to categorize patients into high-risk and low-risk groups, with tumor microenvironment (TME) features analyzed across these subgroups. The pro-tumorigenic role of NRP1 via the TGF-β/SMAD signaling pathway was validated in vitro and in vivo. Results Twelve pFRGs were identified, with elevated expression correlating with reduced survival. NMF revealed two ccRCC subtypes with different fibrotic and immune profiles. The high-fibrosis subtype showed worse survival and a pro-tumorigenic TME. The risk model demonstrated robust predictive performance (AUCs: 0.738, 0.731, 0.711 for 1-, 2-, and 3-year survival). High-risk patients, marked by immune dysfunction, exhibited worse survival but greater immunotherapy sensitivity. Among the pFRGs, NRP1 was upregulated in ccRCC, and paradoxically associated with favorable prognosis in TCGA, primarily due to stromal enrichment. In vitro and in vivo experiments confirmed that NRP1 promotes ccRCC proliferation, migration, and invasion by enhancing TGF-β/SMAD-driven epithelial-mesenchymal transition (EMT). Conclusion Fibrosis is a critical driver of ccRCC progression, linking fibrogenesis-related genes to poor prognosis, immune suppression, and tumor aggressiveness. NRP1 was identified as a central regulator of fibrosis-induced tumor progression through the TGF-β/SMAD signaling pathway. Combining NRP1 inhibition with anti-fibrotic therapies presents a potential strategy for enhancing therapeutic outcomes in ccRCC. Graphical abstract |
| format | Article |
| id | doaj-art-c74587daebc5413295248cb72621e08a |
| institution | OA Journals |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj-art-c74587daebc5413295248cb72621e08a2025-08-20T02:25:12ZengBMCCancer Cell International1475-28672025-05-0125112710.1186/s12935-025-03801-2Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1Kai Wang0Xihao Shen1Jiyue Wu2Qing Bi3Zihao Gao4Zejia Sun5Wei Wang6Department of Urology, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Urology, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Urology, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Urology, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Urology, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Urology, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Urology, Beijing Chao-Yang Hospital, Capital Medical UniversityAbstract Background Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Neuropilin-1 (NRP1), a key mediator in fibrotic signaling and cancer biology, has been implicated in these processes. However, the genetic correlation between fibrogenesis and ccRCC remains largely unexplored, necessitating a focused analysis of fibrogenesis-related genes (FRGs) to identify novel prognostic markers and therapeutic strategies. Methods This study utilized an integrative bioinformatics framework to identify prognosis-associated fibrogenesis-related genes (pFRGs) and applied non-negative matrix factorization (NMF) to stratify ccRCC patients based on fibrotic signatures. A machine learning-derived prognostic model was developed to categorize patients into high-risk and low-risk groups, with tumor microenvironment (TME) features analyzed across these subgroups. The pro-tumorigenic role of NRP1 via the TGF-β/SMAD signaling pathway was validated in vitro and in vivo. Results Twelve pFRGs were identified, with elevated expression correlating with reduced survival. NMF revealed two ccRCC subtypes with different fibrotic and immune profiles. The high-fibrosis subtype showed worse survival and a pro-tumorigenic TME. The risk model demonstrated robust predictive performance (AUCs: 0.738, 0.731, 0.711 for 1-, 2-, and 3-year survival). High-risk patients, marked by immune dysfunction, exhibited worse survival but greater immunotherapy sensitivity. Among the pFRGs, NRP1 was upregulated in ccRCC, and paradoxically associated with favorable prognosis in TCGA, primarily due to stromal enrichment. In vitro and in vivo experiments confirmed that NRP1 promotes ccRCC proliferation, migration, and invasion by enhancing TGF-β/SMAD-driven epithelial-mesenchymal transition (EMT). Conclusion Fibrosis is a critical driver of ccRCC progression, linking fibrogenesis-related genes to poor prognosis, immune suppression, and tumor aggressiveness. NRP1 was identified as a central regulator of fibrosis-induced tumor progression through the TGF-β/SMAD signaling pathway. Combining NRP1 inhibition with anti-fibrotic therapies presents a potential strategy for enhancing therapeutic outcomes in ccRCC. Graphical abstracthttps://doi.org/10.1186/s12935-025-03801-2FibrogenesisClear cell renal cell carcinomaMachine learningNRP1Epithelial-to-mesenchymal transitionTGF-β/SMAD pathway |
| spellingShingle | Kai Wang Xihao Shen Jiyue Wu Qing Bi Zihao Gao Zejia Sun Wei Wang Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1 Cancer Cell International Fibrogenesis Clear cell renal cell carcinoma Machine learning NRP1 Epithelial-to-mesenchymal transition TGF-β/SMAD pathway |
| title | Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1 |
| title_full | Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1 |
| title_fullStr | Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1 |
| title_full_unstemmed | Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1 |
| title_short | Fibrogenesis-driven tumor progression in clear cell renal cell carcinoma: prognostic, therapeutic implications and the dual role of neuropilin-1 |
| title_sort | fibrogenesis driven tumor progression in clear cell renal cell carcinoma prognostic therapeutic implications and the dual role of neuropilin 1 |
| topic | Fibrogenesis Clear cell renal cell carcinoma Machine learning NRP1 Epithelial-to-mesenchymal transition TGF-β/SMAD pathway |
| url | https://doi.org/10.1186/s12935-025-03801-2 |
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