CD70 regulates the NF1/Ras/ERK axis to promote metastatic potential in clear cell renal cell carcinoma.

backgroundDespite significant advances in the treatment of clear cell renal cell carcinoma (ccRCC) over the past two decades, therapeutic intervention for patients at advanced or metastatic stages remains a clinical hurdle. Emerging evidence highlights aberrant CD70 expression during tumor progression, supporting its potential as a therapeutic target in advanced ccRCC. However, the molecular mechanisms underlying CD70-mediated metastatic processes remain poorly defined.

methodsCD70 was knocked out or overexpressed in three ccRCC cell lines, and its role in tumor progression was assessed using in vitro migration and invasion assays, as well as in vivo tumorigenesis and metastasis models. Mass spectrometry-based proteomics was performed to identify differentially expressed proteins and potential pathway dysregulation following CD70 depletion. Co-immunoprecipitation (Co-IP) assays confirmed the CD70-NF1 interaction, and NF1 knockdown in CD70-knockout cells was conducted to reverse the effects of CD70 depletion on Ras/ERK signaling, migration, invasion, and epithelial-mesenchymal transition (EMT)-related features. Expression of EMT-related marks were evaluated by quantitative real-time PCR (qRT-PCR), Western blot, and immunohistochemistry (IHC).

resultsCD70 was significantly upregulated in ccRCC tissues and correlated with poor survival outcomes. CD70 knockout markedly inhibited in vitro cell migration and invasion, as well as in vivo tumor growth and metastasis. Mechanistically, CD70 depletion was associated with increased neurofibromin 1 (NF1) expression in ccRCC cells; CD70 knockout resulted in robust NF1 induction, which in turn suppressed Ras/ERK signaling and downstream EMT-related molecular alterations. Notably, NF1 knockdown largely reversed the inhibitory effects of CD70 knockout on these key molecular and functional phenotype changes.

conclusionsOur findings uncover a novel CD70-NF1-Ras/ERK axis that contributes to ccRCC progression and metastasis, involving suppression of NF1 and subsequent activation of the Ras/ERK signaling pathway, which further promotes EMT and enhances metastatic capacity. These insights provide a mechanistic foundation for targeting CD70 as a potential therapeutic strategy in advanced ccRCC. Notably, we propose that CD70-targeted therapy may be more effective when combined with agents blocking adaptive escape pathways (e.g., Ras/ERK inhibitors), a hypothesis generated by mechanistic rescue and pharmacologic inhibition in vitro, which require further preclinical validation to confirm synergistic efficacy and clinical viability.