Vascular endothelial growth factor B coordinates metastasis of non-small cell lung cancer
- 227 Downloads
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.
KeywordsVascular endothelial growth factor B (VEGF-B) Matrix metalloproteinases 9 (MMP9), PI3K ERK/MAPK Non-small cell lung cancer (NSCLC) Metastasis
Conflicts of interest
- 14.Carrillo de Santa Pau E, Arias FC, Caso Pelaez E, Munoz Molina GM, Sanchez Hernandez I, Muguruza Trueba I, et al. Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer. Cancer. 2009;115:1701–12.CrossRefPubMedGoogle Scholar