Wang Kai, Shen Xihao, Wu Jiyue, Bi Qing, Gao Zihao, Sun Zejia, Wang Wei
Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Department of Urology, Linyi People's Hospital, Linyi, Shandong, China.
Cancer Cell Int. 2025 May 16;25(1):179. doi: 10.1186/s12935-025-03801-2.
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.
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.
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).
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.
透明细胞肾细胞癌（ccRCC）是肾癌的主要亚型，预后较差，存在治疗抵抗及复发倾向。肿瘤微环境（TME）相关纤维化通过促进免疫逃逸加速疾病进展。神经纤毛蛋白-1（NRP1）是纤维化信号传导和癌症生物学中的关键介质，参与了这些过程。然而，纤维化与ccRCC之间的遗传相关性在很大程度上仍未被探索，因此有必要对纤维化相关基因（FRGs）进行重点分析，以确定新的预后标志物和治疗策略。
本研究利用综合生物信息学框架来识别与预后相关的纤维化相关基因（pFRGs），并应用非负矩阵分解（NMF）根据纤维化特征对ccRCC患者进行分层。开发了一种基于机器学习的预后模型，将患者分为高风险和低风险组，并分析这些亚组中的肿瘤微环境（TME）特征。通过体外和体内实验验证了NRP1通过TGF-β/SMAD信号通路的促肿瘤发生作用。
确定了12个pFRGs，其表达升高与生存率降低相关。NMF揭示了两种具有不同纤维化和免疫特征的ccRCC亚型。高纤维化亚型显示出更差的生存率和促肿瘤发生的TME。风险模型显示出强大的预测性能（1年、2年和3年生存率的AUC分别为0.738、0.731、0.711）。以免疫功能障碍为特征的高风险患者生存率较差，但免疫治疗敏感性更高。在pFRGs中，NRP1在ccRCC中上调，在TCGA中与良好预后呈矛盾相关，主要是由于基质富集。体外和体内实验证实，NRP1通过增强TGF-β/SMAD驱动的上皮-间质转化（EMT）促进ccRCC的增殖、迁移和侵袭。
纤维化是ccRCC进展的关键驱动因素，将纤维化相关基因与不良预后、免疫抑制和肿瘤侵袭性联系起来。NRP1被确定为通过TGF-β/SMAD信号通路介导纤维化诱导的肿瘤进展的核心调节因子。将NRP1抑制与抗纤维化治疗相结合是提高ccRCC治疗效果的潜在策略。
