Keap1-Nrf2 Interaction Suppresses Cell Motility in Lung Adenocarcinomas by Targeting the S100P Protein
Authors: Tsu-Yao Cheng
Jin-Shing Chen
Chia-Feng Li
Michael Hsiao
Ming-Yang Wang
Min-Liang Kuo
Yi-Hua Jan
Kuo-Tai Hua
Feng-Koo Hsieh
Jyh-Ming Chow
Ming-Hsien Chien
Wei-Jiunn Lee
Journal: Clinical Cancer Research (2015)
Discipline: CLINICAL MEDICINE
Keywords: Keap1; Nrf2; NSCLC; cancer motility; tumor metastasis
Affiliations: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan., Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan., Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University, Munich, Germany., Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan., Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan., Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan., Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan., The Genomics Research Center, Academia Sinica, Taipei, Taiwan., Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.  ., Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan. Graduate Institute of Biomedical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.  .

Abstract:  Purpose: Kelch-like ECH-associated protein 1 (Keap1) is an E3 ligase participated in the cellular defense response against oxidative stress through nuclear factor erythroid-2-related factor 2 (Nrf2). However, the role of Keap1 in regulating cancer motility is still controversial. We investigated the contribution of the Keap1-Nrf2 axis in the progression of non-small cell lung cancer (NSCLC). Experimental design: The expression of Keap1 and Nrf2 was examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of NSCLC tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of the Keap1-Nrf2 axis in lung cancer mobility and progression. Results: Keap1 expression was decreased in specimens from NSCLC patients with lymph node metastasis compared with patients without metastasis. Higher Keap1 expression levels were correlated with the survival of NSCLC patients. Moreover, manipulation of Keap1 expression affected cell migration/invasion abilities. Depletion of Nrf2 relieved the migration promotion imposed by Keap1 suppression. Mechanistic investigations found that S100P was downregulated in both Keap1-overexpressing and Nrf2-knockdown NSCLC cells. Overexpression of Keap1 and knockdown of Nrf2 both suppressed S100P expression in NSCLC cells. Knockdown of S100P inhibited cell migration in highly invasive NSCLC cells and also relieved the migration promotion imposed by Keap1 suppression in weakly invasive NSCLC cells. Conclusions: Our findings suggest that Keap1 functions as a suppressor of tumor metastasis by targeting the Nrf2/S100P pathway in NSCLC cells. In addition, overexpression of Keap1 may be a novel NSCLC treatment strategy and/or useful biomarker for predicting NSCLC progression. 

Retracted: No

PubPeer comments:
 Figure 6B: duplication of RT-PCR data ![file] Min-Liang Kuo has several retractions and corrections after an investigation at NTU. Apparently this issue was not included... ,