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. Mol Cancer Res; 11(3); 261-71. Ó2012 AACR.

TGF‐β‐mediated exosomal lnc‐MMP2‐2 regulates migration and invasion of lung cancer cells to the vasculature by promoting MMP2 expression

“…Previous studies reported roles for MMP2 in regulating lung cancer invasion and vascular permeability . In the present study, exogenous overexpression and interference experiments showed that lnc‐MMP2‐2 promoted lung cancer invasion and increased vascular permeability, and that lnc‐MMP2‐2 expression was markedly higher in lung cancer tissues than in normal controls.…”

CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo

“…MnSOD was shown promoting breast cancer metastasis and anoikis resistance, 47 as well as enhancing lung cancer cell invasion through upregulating FoxM1 and MMP2 expression. 48 On the other hand, overexpression of MnSOD was shown to inhibit cell proliferation or suppress malignant phenotype of pancreatic cancer cells, 49, 50 breast cancer cells 51 and prostate cancer cells. 51, 52 Furthermore, oncolytic adenovirus carrying gene encoding MnSOD was shown to significantly suppress colon cancer cell growth both in vitro and in vivo through activating the Bax–cytochrome c –caspase-9–caspase-3 apoptotic signaling pathway.…”

RNF168 cooperates with RNF8 to mediate FOXM1 ubiquitination and degradation in breast cancer epirubicin treatment

“…8, 9 The eGFP-FOXM1 and pcDNA3-FOXM1 WT and 5x(K>R) mutant expression plasmids have also been described. 15 The expression vectors for RNF8, 25 RNF168, 30 Flag-RNF168 31 and HA-RNF8 32 have also been described previously. The pcDNA3-RNF4 plasmid was from Prof Ron T. Hay (University of Dundee, Dundee, UK).…”