Dual-negative expression of Nrf2 and NQO1 predicts superior outcomes in patients with non-small cell lung cancer

// Ying-Hui Tong 1, * , Bo Zhang 2, * , You-You Yan 2 , Yun Fan 3 , Jia-Wen Yu 1 , Si-Si Kong 1 , Dan Zhang 2 , Luo Fang 1 , Dan Su 3 and Neng-Ming Lin 2 1 Laboratory of Clinical Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China 2 Laboratory of Clinical Pharmacology, Translational Medicine Research Center, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou, Zhejiang 310006, China 3 Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology (Esophagus, Lung), Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China * These authors have contributed equally to this work Correspondence to: Neng-Ming Lin, email: lnm1013@163.com Keywords: non-small cell lung cancer (NSCLC), NF-E2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase-1 (NQO1), prognosis, dual-negative expression Received: January 12, 2017 Accepted: April 03, 2017 Published: April 25, 2017 ABSTRACT Functional studies in non-small cell lung cancer (NSCLC) patients revealed that hyperactivation of the NF-E2-related factor 2 (Nrf2) pathway facilitates tumor growth. We examined the usefulness of Nrf2 and NQO1 as indicators of prognosis in NSCLC. Tumor and adjacent non-tumor tissue samples were collected from 215 NSCLC patients who had tumor resections between 2006 and 2011. Immunohistochemistry was performed to detect Nrf2 or NQO1 expression. The correlation between Nrf2 or NQO1 expression and survival outcomes was evaluated using the Kaplan-Meier method and Cox proportional hazards regression model. Levels of Nrf2 and NQO1 were elevated in tumor tissues. In particular, Nrf2 was elevated in nearly all tumor cells. NQO1 expression positively correlated with Nrf2 expression ( P = 0.039). Nrf2 expression positively correlated with lymph node metastasis ( P = 0.001) and negatively correlated with tumor differentiation ( P = 0.032). As compared with either Nrf2 or NQO1 alone, dual-negative expression of Nrf2 and NQO1 was more predictive of superior overall survival ( P = 0.020) and disease free survival ( P = 0.037). Subgroup analyses showed that females, nonsmokers, and patients with advanced-stage NSCLC were suitable populations in which to evaluate prognosis based on Nrf2 and NQO1 co-expression. These results indicate that dual-negative expression of Nrf2 and NQO1 is predictive of a better prognosis in NSCLC patients.