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.

Keywords:
Biomarkers, Carcinoma, Renal cell, Inflammation, Nuclear factor-kappa B
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:E359–E86.
2.
Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS, Mulders P, Powles T, Staehler M, Volpe A, Bex A: EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015; 67: 913–924.
3.
Hacker H, Karin M: Regulation and function of IKK and IKK-related kinases. Sci STKE 2006; 2006:re13.
4.
Hoffmann A, Baltimore D: Circuitry of nuclear factor kappaB signaling. Immunol Rev 2006; 210: 171–186.
5.
Karin M, Cao Y, Greten FR, Li ZW: NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002; 2: 301–310.
6.
Duran CL, Lee DW, Jung JU, Ravi S, Pogue CB, Toussaint LG, Bayless KJ, Sitcheran R: NIK regulates MT1-MMP activity and promotes glioma cell invasion independently of the canonical NF-κB pathway. Oncogenesis 2016; 5:e231.
7.
Poveda J, Tabara LC, Fernandez-Fernandez B, Martin-Cleary C, Sanz AB, Selgas R, Ortiz A, Sanchez-Nino MD: TWEAK/Fn14 and non-canonical NF-kappaB signaling in kidney disease. Front Immunol 2013; 4: 447.
8.
Sanz AB, Sanchez-Nino MD, Ortiz A: TWEAK, a multifunctional cytokine in kidney injury. Kidney Int 2011; 80: 708–718.
9.
Sanz AB, Sanchez-Nino MD, Ramos AM, Moreno JA, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A: NF-kappaB in renal inflammation. J Am Soc Nephrol 2010; 21: 1254–1262.
10.
Kirkegaard T, Edwards J, Tovey S, McGlynn LM, Krishna SN, Mukherjee R, Tam L, Munro AF, Dunne B, Bartlett JM: Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology 2006; 48: 787–794.
11.
Ben-Neriah Y, Karin M: Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 2011; 12: 715–723.
12.
Qin H, Zhou J, Zhou P, Xu J, Tang Z, Ma H, Guo F: Prognostic significance of RelB overexpression in non-small cell lung cancer patients. Thorac Cancer 2016; 7: 415–421.
13.
Rojo F, Gonzalez-Perez A, Furriol J, Nicolau MJ, Ferrer J, Burgues O, Sabbaghi M, Gonzalez-Navarrete I, Cristobal I, Serrano L, Zazo S, Madoz J, Servitja S, Tusquets I, Albanell J, Lluch A, Rovira A, Eroles P: Non-canonical NF-κB pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma. Br J Cancer 2016; 115: 322–331.
14.
Shen M, Duan X, Zhou P, Zhou W, Wu X, Xu S, Chen Y, Tao Z: Lymphotoxin beta receptor activation promotes bladder cancer in a nuclear factor-kappaB-dependent manner. Mol Med Rep 2015; 11: 783–790.
15.
Sanz AB, Sanchez-Nino MD, Izquierdo MC, Jakubowski A, Justo P, Blanco-Colio LM, Ruiz-Ortega M, Selgas R, Egido J, Ortiz A: TWEAK activates the non-canonical NFkappaB pathway in murine renal tubular cells: modulation of CCL21. PLoS One 2010; 5:e8955.
16.
Feng B, Chen G, Zheng X, Sun H, Zhang X, Zhang ZX, Xiang Y, Ichim TE, Garcia B, Luke P, Jevnikar AM, Min WP: Small interfering RNA targeting RelB protects against renal ischemia-reperfusion injury. Transplantation 2009; 87: 1283–1289.
17.
Labrousse-Arias D, Martinez-Alonso E, Corral-Escariz M, Bienes-Martinez R, Berridy J, Serrano-Oviedo L, Conde E, Garcia-Bermejo ML, Gimenez-Bachs JM, Salinas-Sanchez AS, Sanchez-Prieto R, Yao M, Lasa M, Calzada MJ: VHL promotes immune response against renal cell carcinoma via NF-κB-dependent regulation of VCAM-1. J Cell Biol 2017; 216: 835–847.
18.
Dejardin E: The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 2006; 72: 1161–1179.
© 2018 S. Karger AG, Basel
2018
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.