Nuclear NADPH oxidase-4 (Nox4) is a key component of metabolic reprogramming and is often overexpressed in renal cell carcinoma (RCC). However, its prognostic role in RCC remains unclear. Here we examined the significance of nuclear Nox4 on disease progression and development of drug resistance in advanced RCC. We analyzed human RCC tissue from multiple regions in the primary index tumor, cancer-associated normal adjacent parenchyma, intravascular tumor in locally advanced cancer patients. We found that the higher nuclear Nox4 expression was significantly associated with progression and death. These findings were consistent after controlling for other competing clinical variables. In contrast, patients with lower nuclear Nox4, even in higher stage RCC had better prognosis. We identified a subset of patients with high nuclear Nox4 who had rapid disease progression or died within 6 months of surgery. In addition, higher nuclear Nox4 level correlated with resistance to targeted therapy and immunotherapy. Western blotting performed on fresh human RCC tissue as well as cell-lines revealed increased nuclear Nox4 expression. Our data support an important prognostic role of Nox4 mediated regulation of RCC independent of other competing variables. Nox4 localizes to the nucleus in high-grade, high-stage RCC. Higher nuclear Nox4 has prognostic significance for disease progression, poor survival and development of drug resistance in RCC.
Translational research : the journal of laboratory and clinical medicine. 2020 May 31 [Epub ahead of print]
Dharam Kaushik, Keith A Ashcraft, Hanzhang Wang, Karthigayan Shanmugasundaram, Pankil Shah, Gabriela Gonzalez, Alia Nazarullah, Cooper B Tye, Michael A Liss, Deepak Pruthi, Ahmed M Mansour, Wasim Chowdhury, Dean Bacich, Hao Zhang, Amanda L Watson, Karen Block, Denise O'Keefe, Ronald Rodriguez
Department of Urology, University of Texas Health, San Antonio, TX. Electronic address: ., Department of Urology, University of Texas Health, San Antonio, TX., Department of Molecular Medicine, University of Texas Health, San Antonio, TX., Department of Pathology, University of Texas Health, San Antonio, TX., Department of Cellular and Molecular Medicine, University of Arizona, Phoenix, AZ., Office of Research and Development, Veteran Affairs, Washington DC.