The role of SOD2 in lung tumor progression

• Main Authors: Po-Ming Chen, 陳柏銘
• Other Authors: 許 國 堂
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/86574519966822669043

博士 === 中山醫學大學 === 醫學研究所 === 101 === MnSOD (SOD2) has been shown to cause dysfunction of p53 transcriptional activity, while conversely, SOD2 expression is further regulated by p53 to modulate lung tumorigenesis. However, the underlying mechanism remains elusive. In the present study, SOD2 expression in a panel of lung cancer cells was negatively correlated with NKX2-1, but not related with p53 status. We demonstrated that NKX2-1 may act a direct transcription factor to upregulate p53 transcription. Mechanistic studies indicated a decrease in NKX2-1 caused by SOD2 activated IKKβ transcription by de-repression of the binding activity of SP1 to the IKKβ promoter due to suppression of p53 function. In addition, immunoprecipitation, GST-pull down, and EMSA assays demonstrated a direct interaction between NKX2-1 and Sp1, which blocked Sp1-mediated IKKβ transcription. SOD2-mediated NF-κB activation via elevation of IKKβ transcription promoted anchorage-independent soft-agar growth, invasion capability, and xenograft tumor formation. We further investigated the possibility that FOXM1 and MMP2 elevated by SOD2 could be responsible for migration, soft-agar growth and invasion capability in lung adenocarcinoma cells. Western blotting showed that FOXM1 and MMP2 expression was dependent on SOD2 expression. Luciferase gene reporter and chromatin immunoprecipitation assays indicated that SOD2 overexpression in lung cancer cells promoted E2F1 and Sp1 binding to FOXM1 promoter and activated reporter activity due to p53 function suppressed by SOD2 overexpression. SOD2 enhanced the potential for cell migration, invasion, and soft agar growth via the FOXM1-MMP-2 axis. In lung adenocarcinoma patients, the expression of NKX2-1 mRNA was negatively associated with SOD2 immunostaining and with IKKβ mRNA expression levels in lung tumors. SOD2 immunostaining and IKKβ mRNA levels could independently predict overall survival and relapse-free survival in lung adenocarcinoma patients. We therefore demonstrated that SOD2 activates IKKβ/NF-kB and FOXM1-MMP2 axis, which results in lung adenocarcinoma progression and poorer patient outcomes.