MMP9 activation triggered by epidermal growth factor induced FoxO1 nuclear exclusion in non-small cell lung cancer

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• 作者：Jun Pei (1)
  Yuqing Lou (1)
  Runbo Zhong (1)
  Baohui Han (1)
  
• 关键词：Epidermal growth factor ; PI3 kinase ; FoxO1 ; Non ; small cell lung cancer ; MMP9 ; Cancer invasiveness ; Cancer metastasis
• 刊名：Tumor Biology
• 出版年：2014
• 出版时间：July 2014
• 年：2014
• 卷：35
• 期：7
• 页码：6673-6678
• 全文大小：371 KB
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• 作者单位：Jun Pei (1)
  Yuqing Lou (1)
  Runbo Zhong (1)
  Baohui Han (1)
  
  1. Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
  
• ISSN：1423-0380

文摘

The molecular mechanism underlying activation of matrix metallopeptidase 9 (MMP9) in non-small cell lung cancer (NSCLC) cells, which controls cancer invasiveness and metastasis, remains elusive. Here, we reported a strong correlation of epidermal growth factor receptor (EGFR) and MMP9 levels in NSCLC patients. Thus, we used a human NSCLC line, A549, to examine whether there is a causal link between EGFR and MMP9 activation. We found that EGF-induced activation of EGFR in A549 cells activated MMP9, resulting in an increase in cancer invasiveness. An EGFR inhibitor efficiently blocked this EGF-induced activation of MMP9 and, consequently, increased cancer invasiveness. Moreover, an inhibitor for phosphatidylinositol 3-kinase (PI3K)/Akt, but not an inhibitor for mitogen-activated protein kinase, or an inhibitor for Jun N-terminal kinase, significantly inhibited the epidermal growth factor (EGF)-induced activation of MMP9, suggesting that PI3K/Akt signaling cascades may be responsible for EGF-activated MMP9. We further dissected the pathway and found that nuclear exclusion of a major Akt downstream target, FoxO1, occurred by EGF-induced Akt activation, which could be inhibited by either EGFR inhibitor or by PI3K/Akt inhibitor. In a loss of function, expression of a constitutive nuclear form of FoxO1 significantly inhibited MMP9 activation induced by EGF. Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI3K/Akt to induce FoxO1 nuclear exclusion, which activates MMP9 to promote NSCLC invasiveness. Thus, Akt and FoxO1, in addition to the well-known EGFR, appear to be promising therapeutic targets for preventing the metastasis of NSCLC.