Keap1-Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein

Ming Hsien Chien, Wei Jiunn Lee, Feng Koo Hsieh, Chia Feng Li, Tsu Yao Cheng, Ming Yang Wang, Jin Shing Chen, Jyh Ming Chow, Yi Hua Jan, Michael Hsiao, Kuo Tai Hua, Min Liang Kuo

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4719-4732
Number of pages14
JournalClinical Cancer Research
Volume21
Issue number20
DOIs
Publication statusPublished - Oct 15 2015

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Protein Transport
Cell Movement
Non-Small Cell Lung Carcinoma
Neoplasm Metastasis
Kelch-Like ECH-Associated Protein 1
Adenocarcinoma of lung
Ubiquitin-Protein Ligases
Real-Time Polymerase Chain Reaction
Lung Neoplasms
Neoplasms
Oxidative Stress
Research Design
Down-Regulation
Biomarkers
Lymph Nodes
Western Blotting
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Keap1-Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein. / Chien, Ming Hsien; Lee, Wei Jiunn; Hsieh, Feng Koo; Li, Chia Feng; Cheng, Tsu Yao; Wang, Ming Yang; Chen, Jin Shing; Chow, Jyh Ming; Jan, Yi Hua; Hsiao, Michael; Hua, Kuo Tai; Kuo, Min Liang.

In: Clinical Cancer Research, Vol. 21, No. 20, 15.10.2015, p. 4719-4732.

Research output: Contribution to journalArticle

Chien, MH, Lee, WJ, Hsieh, FK, Li, CF, Cheng, TY, Wang, MY, Chen, JS, Chow, JM, Jan, YH, Hsiao, M, Hua, KT & Kuo, ML 2015, 'Keap1-Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein', Clinical Cancer Research, vol. 21, no. 20, pp. 4719-4732. https://doi.org/10.1158/1078-0432.CCR-14-2880
Chien, Ming Hsien ; Lee, Wei Jiunn ; Hsieh, Feng Koo ; Li, Chia Feng ; Cheng, Tsu Yao ; Wang, Ming Yang ; Chen, Jin Shing ; Chow, Jyh Ming ; Jan, Yi Hua ; Hsiao, Michael ; Hua, Kuo Tai ; Kuo, Min Liang. / Keap1-Nrf2 interaction suppresses cell motility in lung adenocarcinomas by targeting the S100P protein. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 20. pp. 4719-4732.
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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.",
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AU - Chien, Ming Hsien

AU - Lee, Wei Jiunn

AU - Hsieh, Feng Koo

AU - Li, Chia Feng

AU - Cheng, Tsu Yao

AU - Wang, Ming Yang

AU - Chen, Jin Shing

AU - Chow, Jyh Ming

AU - Jan, Yi Hua

AU - Hsiao, Michael

AU - Hua, Kuo Tai

AU - Kuo, Min Liang

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AB - 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.

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