title: Placental growth factor promotes metastases of non-small cell lung cancer through MMP9.
abstract: OBJECTIVE
  Neovascularization and invasion coordinate cancer metastases in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms are poorly understood. Recently, a substantial role of placental growth factor (PLGF) in cancer cell invasion has been acknowledged in several types of cancer, whereas a possible involvement of PLGF in the metastases of NSCLC has not been studied.
  
  
  METHODS
  Here, we analyzed the levels of PLGF and matrix metalloproteinase 9 (MMP9) in NSCLC specimens. We modified either PLGF or MMP9 levels in a NSCLC cell line A549, and examined the effects on the levels of MMP9 and PLGF. The cell invasiveness was quantified in a transwell cell migration assay. Pathway inhibitors were applied to determine the molecular mechanisms underlying the control of MMP9 by PLGF.
  
  
  RESULTS
  We found that PLGF and MMP9 levels both significantly increased in the NSCLC specimens and were strongly correlated. Overexpression of PLGF in NSCLC cells increased the levels of MMP9 and cell invasiveness, while inhibition of PLGF in NSCLC cells decreased the levels of MMP9 and cell invasiveness. However, modification of MMP9 levels in NSCLC cells did not alter the levels of PLGF. These data suggest that PLGF may regulate MMP9 in NSCLC cells, but not vice versa. Moreover, inhibition of MMP9 in PLGF-overexpressing NSCLC cells abolished the effects of PLGF on cell invasiveness, suggesting that PLGF increases cell invasion via MMP9. Furthermore, suppression of MAPK-p38, but not suppression of either MAPK-p42/p44, or PI3k, or JNK signaling, substantially abolished the effect of PLGF on MMP9, suggesting that PLGF may activate MMP9 via MAPK-p38 signaling pathway.
  
  
  CONCLUSIONS
  PLGF-stimulated cancer invasion may be mediated through its effects on MMP9 activation in NSCLC cells.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Lou
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.forename: Shaohua
authors.initials: S
authors.lastname: Cui
authors.forename: Liyan
authors.initials: L
authors.lastname: Jiang
authors.forename: Baohui
authors.initials: B
authors.lastname: Han
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000097:blood* / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood* / Q000235:genetics
chemical_list: C000608036:PGF protein, human; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9