Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2-1-mediated IKKβ expression

Po Ming Chen, Tzu Chin Wu, Yao Chen Wang, Ya Wen Cheng, Gwo Tarng Sheu, Chih Yi Chen, Huei Lee

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Magnesium superoxide dismutase (SOD2) has been shown to cause dysfunction of p53 transcriptional activity, whereas, in turn, SOD2 expression is regulated by p53 to modulate lung tumorigenesis. In this study, we found that the level of SOD2 expression in a panel of lung cancer cells was negatively correlated with that of NK2 homeobox 1 (NKX2-1) but was not associated with p53 status. Mechanistic studies indicated that a decrease in NKX2-1 caused by SOD2-activated IKKβ transcription was achieved by derepression of binding of Sp1 to the IKKβ promoter. Immunoprecipitation, glutathione S-transferase pull-down experiments and electrophoretic mobility shift assays demonstrated a direct interaction between NKX2-1 and Sp1, blocking Sp1-mediated IKKβ transcription. SOD2-mediated nuclear factor-kappaB activation, via elevation of IKKβ transcription, promoted anchorage-independent soft-agar growth, invasion and xenograft tumor formation, because of development of the epithelial-to-mesenchymal transition. The expression level of NKX2-1 messenger RNA was negatively associated with the extent of SOD immunostaining and the IKKβ messenger RNA expression level in lung tumors. The extent of SOD2 immunostaining and IKKβ messenger RNA levels may independently predict overall survival and relapse-free survival in lung adenocarcinoma patients. In summary, we found that SOD2 activates nuclear factor-kappaB signaling by increasing IKKβ transcription, which results in progression of lung adenocarcinoma and poorer patient outcomes. We suggest that IKKβ may potentially be targeted to improve outcomes in patients with SOD2-positive tumors.

Original languageEnglish
Pages (from-to)2655-2663
Number of pages9
JournalCarcinogenesis
Volume34
Issue number11
DOIs
Publication statusPublished - Nov 2013

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Messenger RNA
Neoplasms
Lung
Epithelial-Mesenchymal Transition
Survival
Homeobox Genes
Electrophoretic Mobility Shift Assay
Glutathione Transferase
Immunoprecipitation
Heterografts
Magnesium
Superoxide Dismutase
Agar
Lung Neoplasms
Carcinogenesis
Recurrence
Growth
Adenocarcinoma of lung

ASJC Scopus subject areas

  • Cancer Research

Cite this

Chen, P. M., Wu, T. C., Wang, Y. C., Cheng, Y. W., Sheu, G. T., Chen, C. Y., & Lee, H. (2013). Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2-1-mediated IKKβ expression. Carcinogenesis, 34(11), 2655-2663. https://doi.org/10.1093/carcin/bgt220

Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2-1-mediated IKKβ expression. / Chen, Po Ming; Wu, Tzu Chin; Wang, Yao Chen; Cheng, Ya Wen; Sheu, Gwo Tarng; Chen, Chih Yi; Lee, Huei.

In: Carcinogenesis, Vol. 34, No. 11, 11.2013, p. 2655-2663.

Research output: Contribution to journalArticle

Chen, Po Ming ; Wu, Tzu Chin ; Wang, Yao Chen ; Cheng, Ya Wen ; Sheu, Gwo Tarng ; Chen, Chih Yi ; Lee, Huei. / Activation of NF-κB by SOD2 promotes the aggressiveness of lung adenocarcinoma by modulating NKX2-1-mediated IKKβ expression. In: Carcinogenesis. 2013 ; Vol. 34, No. 11. pp. 2655-2663.
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