Background: In the United Kingdom, 8,000 cases of renal cancer are diagnosed each year, with a 5-year survival rate of 50%. Treatment options are limited; a potential therapeutic target is the non-canonical nuclear factor-kappa B (NF-κB) pathway. This pathway plays a role in multiple oncogenic processes in solid tumors. The aim of this study was to investigate the non-canonical nuclear factor pathway in renal cell carcinoma (RCC). Materials and Methods: NIK, IKKα, and RelB were investigated via immunohistochemistry in a cohort of 192 patients with clear cell renal cancer. Results: High cytoplasmic NIK was associated with poorer cancer-specific survival (p = 0.006) and 10-year survival stratified from 85% (low) to 65% (high, p = 0.005). Similarly, high cytoplasmic RelB was associated with poorer cancer-specific survival (p = 0.041) and 10-year survival stratified from 88% (low) to 73% (high, p = 0.030). When clinicopathological characteristics were assessed, cytoplasmic NIK was associated with survival (p = 0.014), whereas cytoplasmic RelB was associated with increased tumor grade (p = 0.020) and decreased inflammation (p = 0.019). Upon multivariate analysis, it was found that cytoplasmic NIK was independently associated with cancer-specific survival (p = 0.009). Conclusions: The non-canonical NF-κB pathway is associated with poorer cancer-specific survival in RCC patients, making it a viable target for therapeutic intervention. Furthermore, cytoplasmic NIK is a potential prognostic biomarker for this disease.

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