TY - JOUR
T1 - Nuclear NADPH oxidase-4 associated with disease progression in renal cell carcinoma
AU - Kaushik, Dharam
AU - Ashcraft, Keith A.
AU - Wang, Hanzhang
AU - Shanmugasundaram, Karthigayan
AU - Shah, Pankil K.
AU - Gonzalez, Gabriela
AU - Nazarullah, Alia
AU - Tye, Cooper B.
AU - Liss, Michael A.
AU - Pruthi, Deepak K.
AU - Mansour, Ahmed M.
AU - Chowdhury, Wasim
AU - Bacich, Dean
AU - Zhang, Hao
AU - Watson, Amanda L.
AU - Block, Karen
AU - O'Keefe, Denise
AU - Rodriguez, Ronald
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.trsl.2020.05.009
DO - 10.1016/j.trsl.2020.05.009
M3 - Article
C2 - 32492552
AN - SCOPUS:85087040298
VL - 223
SP - 1
EP - 14
JO - Translational Research
JF - Translational Research
SN - 1931-5244
ER -