Astrocyte elevated gene-1 increases invasiveness of NSCLC through up-regulating MMP7

Cell Physiol Biochem. 2015;37(3):1187-95. doi: 10.1159/000430242. Epub 2015 Sep 29.

Abstract

Background/aims: The aggressive manner of non-small cell lung cancer (NSCLC) cells accounts for the majority of the lethality of the disease. Recently, increased astrocyte elevated gene-1 (AEG-1) levels have been shown to closely correlate with poor prognosis of NSCLC, whereas the underlying mechanisms are not clear.

Methods: We examined the AEG-1 and matrix metalloproteinase 7 (MMP7) levels in NSCLC tissues, compared to the paired adjacent non-tumor lung tissue. We modulated AEG-1 levels in NSCLC cells, and examined its effects on MMP7 levels by RT-qPCR, on cellular protein by Western blot, and on secreted protein by ELISA. We also examined the cell invasiveness in AEG-1-modified NSCLC cells in a transwell cell migration assay. We used specific signal pathway inhibitors to treat AEG-1-modified NSCLC cells and examined its effects on MMP7.

Results: AEG-1 and MMP7 levels were both significantly increased in NSCLC tissues, compared to the paired adjacent non-tumor lung tissue. The AEG-1 and MMP7 levels were strongly correlated. Overexpression of AEG-1 in NSCLC cells significantly increased MMP7 levels and cell invasiveness, while AEG-1 depletion in NSCLC cells significantly decreased MMP7 levels and cell invasiveness. Application of a specific MAPK-p42/p44 inhibitor, but not application of specific inhibitors for MAPK-p38, PI3k/Akt, or JNK signaling pathways, to AEG-1-overexpressing NSCLC cells substantially abolished the AEG-1-mediated MMP7 up regulation.

Conclusion: AEG-1 promotes NSCLC cell invasiveness through MAPK-p42/p44-dependent activation of MMP7.

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Matrix Metalloproteinase 7 / genetics*
  • Matrix Metalloproteinase 7 / metabolism
  • Membrane Proteins
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Neoplasm Invasiveness
  • RNA-Binding Proteins
  • Signal Transduction
  • Up-Regulation*

Substances

  • Cell Adhesion Molecules
  • MTDH protein, human
  • Membrane Proteins
  • RNA-Binding Proteins
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MMP7 protein, human
  • Matrix Metalloproteinase 7