title: MnSOD promotes tumor invasion via upregulation of FoxM1-MMP2 axis and related with poor survival and relapse in lung adenocarcinomas.
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.
authors.affiliation: Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Po-Ming
authors.initials: PM
authors.lastname: Chen
authors.forename: Tzu-Chin
authors.initials: TC
authors.lastname: Wu
authors.forename: Shwn-Huey
authors.initials: SH
authors.lastname: Shieh
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Wu
authors.forename: Min-Chin
authors.initials: MC
authors.lastname: Li
authors.forename: Gwo-Tarng
authors.initials: GT
authors.lastname: Sheu
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Cheng
authors.forename: Chih-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D002465:Cell Movement; D018572:Disease-Free Survival; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012008:Recurrence; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D015854:Up-Regulation
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D013482:Superoxide Dismutase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2