MnSOD promotes tumor invasion via upregulation of FoxM1-MMP2 axis and related with poor survival and relapse in lung adenocarcinomas

Po Ming Chen, Tzu Chin Wu, Shwn Huey Shieh, Yi Hui Wu, Min Chin Li, Gwo Tarng Sheu, Ya Wen Cheng, Chih Yi Chen, Huei Lee

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme responsible for the elimination of superoxide radical. The role of MnSOD in tumor progression in different human cancers is still controversial. In the present study, MnSOD expression in lung cancer cells was explored by knockdown or overexpression using transfection of a short hairpin RNA (shRNA) or an expression vector, respectively, to determine whether MnSOD expression mediates lung cancer cell migration, invasion, and oncogenic potential by increasing FoxM1 and MMP2 expression. Western blotting showed that FoxM1 and MMP2 expression was dependent on MnSOD expression, suggesting that FoxM1 could be upregulated by MnSOD. Three FoxM1 promoters were constructed to verify this activation of FoxM1 by MnSOD and to determine the transcription factors responsible. Luciferase reporter and chromatin immunoprecipitation assays indicated that MnSOD overexpression in lung cancer cells promoted binding of E2F1 and Sp1 to their putative FoxM1 promoter-binding sites and activated FoxM1 reporter activity. MnSOD also enhanced the potential for cell migration, invasion, and anchorage-independent colony growth on soft-agar plates, again via upregulation of FoxM1 and MMP2 expression. In patients with lung cancer, evaluation of MnSOD expression in lung tumors by immunohistochemistry indicated a positive correlation between FoxM1 and MMP2 mRNA expressions. Kaplan-Meier and Cox regression analysis revealed a poorer overall survival (OS) and relapse-free survival (RFS) in patients with MnSOD-positive tumors than with MnSOD-negative tumors. We conclude that MnSOD may promote tumor aggressiveness via upregulation of the FoxM1-MMP2 axis, and that MnSOD expression can independently predict survival and relapse in patients with resected lung adenocarcinoma.

Original languageEnglish
Pages (from-to)261-271
Number of pages11
JournalMolecular Cancer Research
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 2013

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Superoxide Dismutase
Up-Regulation
Recurrence
Survival
Neoplasms
Lung Neoplasms
Adenocarcinoma of lung
Cell Movement
Chromatin Immunoprecipitation
Luciferases
Superoxides
Small Interfering RNA
Agar
Transfection
Transcription Factors
Antioxidants
Western Blotting
Immunohistochemistry
Binding Sites
Regression Analysis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

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MnSOD promotes tumor invasion via upregulation of FoxM1-MMP2 axis and related with poor survival and relapse in lung adenocarcinomas. / Chen, Po Ming; Wu, Tzu Chin; Shieh, Shwn Huey; Wu, Yi Hui; Li, Min Chin; Sheu, Gwo Tarng; Cheng, Ya Wen; Chen, Chih Yi; Lee, Huei.

In: Molecular Cancer Research, Vol. 11, No. 3, 03.2013, p. 261-271.

Research output: Contribution to journalArticle

Chen, Po Ming ; Wu, Tzu Chin ; Shieh, Shwn Huey ; Wu, Yi Hui ; Li, Min Chin ; Sheu, Gwo Tarng ; Cheng, Ya Wen ; Chen, Chih Yi ; Lee, Huei. / MnSOD promotes tumor invasion via upregulation of FoxM1-MMP2 axis and related with poor survival and relapse in lung adenocarcinomas. In: Molecular Cancer Research. 2013 ; Vol. 11, No. 3. pp. 261-271.
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abstract = "Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme responsible for the elimination of superoxide radical. The role of MnSOD in tumor progression in different human cancers is still controversial. In the present study, MnSOD expression in lung cancer cells was explored by knockdown or overexpression using transfection of a short hairpin RNA (shRNA) or an expression vector, respectively, to determine whether MnSOD expression mediates lung cancer cell migration, invasion, and oncogenic potential by increasing FoxM1 and MMP2 expression. Western blotting showed that FoxM1 and MMP2 expression was dependent on MnSOD expression, suggesting that FoxM1 could be upregulated by MnSOD. Three FoxM1 promoters were constructed to verify this activation of FoxM1 by MnSOD and to determine the transcription factors responsible. Luciferase reporter and chromatin immunoprecipitation assays indicated that MnSOD overexpression in lung cancer cells promoted binding of E2F1 and Sp1 to their putative FoxM1 promoter-binding sites and activated FoxM1 reporter activity. MnSOD also enhanced the potential for cell migration, invasion, and anchorage-independent colony growth on soft-agar plates, again via upregulation of FoxM1 and MMP2 expression. In patients with lung cancer, evaluation of MnSOD expression in lung tumors by immunohistochemistry indicated a positive correlation between FoxM1 and MMP2 mRNA expressions. Kaplan-Meier and Cox regression analysis revealed a poorer overall survival (OS) and relapse-free survival (RFS) in patients with MnSOD-positive tumors than with MnSOD-negative tumors. We conclude that MnSOD may promote tumor aggressiveness via upregulation of the FoxM1-MMP2 axis, and that MnSOD expression can independently predict survival and relapse in patients with resected lung adenocarcinoma.",
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