@article{1456c62944734b1f86ec16f3857127ae,
title = "Nuclear NADPH oxidase-4 associated with disease progression in renal cell carcinoma",
abstract = "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.",
author = "Dharam Kaushik and Ashcraft, {Keith A.} and Hanzhang Wang and Karthigayan Shanmugasundaram and Shah, {Pankil K.} and Gabriela Gonzalez and Alia Nazarullah and Tye, {Cooper B.} and Liss, {Michael A} and Pruthi, {Deepak K.} and Mansour, {Ahmed M.} and Wasim Chowdhury and Dean Bacich and Hao Zhang and Watson, {Amanda L.} and Karen Block and Denise O'Keefe and Ronald Rodriguez",
note = "Funding Information: Financial support: This project was supported by a grant from the Littenberg Foundation to DK. The content is solely the responsibility of the authors and does not necessarily represent the views of the Littenberg Foundation. Funding Information: The authors have declared that no conflict of interest exists. The manuscript was copy-edited by Susan Albrecht at MedSurgBio Ltd. All authors have read the journal's authorship agreement and policy on disclosure of potential conflicts of interest. We believe that neither the manuscript nor the study violates any of these. There are no conflicts of interest to declare. All authors have read the journal's authorship agreement and that the manuscript has been reviewed by and approved by all named authors. All authors have read the journal's policy on disclosure of potential conflicts of interest. There are no conflict of interest by any authors. Financial support: This project was supported by a grant from the Littenberg Foundation to DK. The content is solely the responsibility of the authors and does not necessarily represent the views of the Littenberg Foundation. Keith A. Ashcraft is supported by a postdoctoral fellowship from the Institutional Research and Career Development Award (K12 GM111726) funded by the NIH/NIGMS. Tissue Microarray (TMA) construction as well as Aperio imaging was performed using the UT Health San Antonio Mays Cancer Center Genomics Shared Resource Facility (NCI P30 CA054174) that also receives institutional support. Data sharing: Data are available for bona fide researchers who request them from the authors. Funding Information: Keith A. Ashcraft is supported by a postdoctoral fellowship from the Institutional Research and Career Development Award (K12 GM111726) funded by the NIH/NIGMS. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = sep,
doi = "10.1016/j.trsl.2020.05.009",
language = "English (US)",
volume = "223",
pages = "1--14",
journal = "Translational Research",
issn = "1931-5244",
publisher = "Mosby Inc.",
}