title: Vascular endothelial growth factor B coordinates metastasis of non-small cell lung cancer.
abstract: Neovascularization is critical for the invasion and metastasis of non-small cell lung cancer (NSCLC). However, the molecular mechanism underlying the control of neovascularization of NSCLC is not completely understood. Both vascular endothelial growth factor B (VEGF-B) and matrix metalloproteinases 9 (MMP9) play essential roles in neovascularization of NSCLC. Here, we examined whether VEGF-B and MMP9 may affect each other to coordinate the neovascularization process in NSCLC. We found strong positive correlation of VEGF-B and MMP9 levels in the NSCLC from the patients. Moreover, patients that had NSCLC with metastasis had significantly higher levels of VEGF-B and MMP9 in the primary cancer. Using a human NSCLC line A549, we found that overexpression of VEGF-B increased expression of MMP9, while inhibition of VEGF-B decreased expression of MMP9. On the other hand, overexpression of MMP9 increased expression of VEGF-B, while inhibition of MMP9 decreased expression of VEGF-B. These data suggest that expression of VEGF-B and MMP9 may activate each other to enhance neovascularization. We then analyzed the underlying mechanism. Application of a specific ERK/MAPK inhibitor but not a PI3K/Akt inhibitor to VEGF-B-overexpressing A549 cells substantially abolished the effect of VEGF-B on MMP9 activation, while application of a specific PI3K/Akt inhibitor but not an ERK/MAPK inhibitor to MMP9-overexpressing A549 cells substantially abolished the effect of MMP9 on VEGF-B activation, suggesting that VEGF-B may activate MMP9 via ERK/MAPK signaling pathway, while MMP9 may activate VEGF-B via PI3K/Akt signaling pathway. Thus, our data highlight a coordinating relationship between VEGF-B and MMP9 in the regulation of neovascularization in NSCLC.
authors.affiliation: Department of Throatic Surgery, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200085, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Shengbao
authors.initials: S
authors.lastname: Xu
authors.forename: Fanglei
authors.initials: F
authors.lastname: Jiao
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.forename: Qinchuan
authors.initials: Q
authors.lastname: Li
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics*
chemical_list: D042561:Vascular Endothelial Growth Factor B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9