MnSOD Promotes Tumor Invasion via Upregulation of FoxM1-MMP2 Axis and Related with Poor Survival and Relapse in Lung Adenocarcinomas
MnSOD Promotes Tumor Invasion via Upregulation of FoxM1-MMP2 Axis and Related with Poor Survival and Relapse in Lung Adenocarcinomas
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DOI：
10.1158/1541-7786.mcr-12-0527
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发表时间：
2013-03-01
影响因子：
5.2
通讯作者：
Lee, Huei
中科院分区：
文献类型：
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作者：
Chen, Po-Ming;Wu, Tzu-Chin;Lee, Huei
锰超氧化物歧化酶（MnSOD）是一种抗氧化酶，负责消除超氧自由基。 MnSOD 在不同人类癌症的肿瘤进展中的作用仍存在争议。在本研究中，通过分别使用短发夹RNA（shRNA）或表达载体转染来敲低或过表达来探索肺癌细胞中MnSOD的表达，以确定MnSOD表达是否通过增加FoxM1和MMP2表达来介导肺癌细胞迁移、侵袭和致癌潜力。 Western blotting显示FoxM1和MMP2的表达依赖于MnSOD的表达，表明MnSOD可以上调FoxM1。构建了三个 FoxM1 启动子来验证 MnSOD 对 FoxM1 的激活并确定负责的转录因子。荧光素酶报告基因和染色质免疫沉淀分析表明，肺癌细胞中 MnSOD 过表达促进了 E2F1 和 Sp1 与其假定的 FoxM1 启动子结合位点的结合，并激活了 FoxM1 报告基因活性。 MnSOD 还通过上调 FoxM1 和 MMP2 的表达，增强了软琼脂平板上细胞迁移、侵袭和不依赖贴壁的集落生长的潜力。在肺癌患者中，通过免疫组织化学评估肺部肿瘤中的 MnSOD 表达表明 FoxM1 和 MMP2 mRNA 表达之间呈正相关。 Kaplan-Meier 和 Cox 回归分析显示，与 MnSOD 阴性肿瘤患者相比，MnSOD 阳性肿瘤患者的总生存期 (OS) 和无复发生存期 (RFS) 较差。我们得出的结论是，MnSOD 可能通过上调 FoxM1-MMP2 轴来促进肿瘤侵袭性，并且 MnSOD 表达可以独立预测已切除肺腺癌患者的生存和复发。摩尔癌症研究中心； 11(3)； 261-71。 (C)2012 AACR。
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. (C)2012 AACR.