Neuropilin-2 expression promotes TGF-beta1-mediated epithelial to mesenchymal transition in colorectal cancer cells.
Fiche publication
Date publication
janvier 2011
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BOIREAU Wilfrid, Pr BORG Christophe, Dr FERRAND Christophe
Tous les auteurs :
Grandclement C, Pallandre JR, Valmary Degano S, Viel E, Bouard A, Balland J, Remy-Martin JP, Simon B, Rouleau A, Boireau W, Klagsbrun M, Ferrand C, Borg C
Lien Pubmed
Résumé
Neuropilins, initially characterized as neuronal receptors, act as co-receptors for cancer related growth factors and were recently involved in several signaling pathways leading to cytoskeletal organization, angiogenesis and cancer progression. Then, we sought to investigate the ability of neuropilin-2 to orchestrate epithelial-mesenchymal transition in colorectal cancer cells. Using specific siRNA to target neuropilin-2 expression, or gene transfer, we first observed that neuropilin-2 expression endows HT29 and Colo320 for xenograft formation. Moreover, neuropilin-2 conferred a fibroblastic-like shape to cancer cells, suggesting an involvement of neuropilin-2 in epithelial-mesenchymal transition. Indeed, the presence of neuropilin-2 in colorectal carcinoma cell lines was correlated with loss of epithelial markers such as cytokeratin-20 and E-cadherin and with acquisition of mesenchymal molecules such as vimentin. Furthermore, we showed by surface plasmon resonance experiments that neuropilin-2 is a receptor for transforming-growth factor-beta1. The expression of neuropilin-2 on colon cancer cell lines was indeed shown to promote transforming-growth factor-beta1 signaling, leading to a constitutive phosphorylation of the Smad2/3 complex. Treatment with specific TGFbeta-type1 receptor kinase inhibitors restored E-cadherin levels and inhibited in part neuropilin-2-induced vimentin expression, suggesting that neuropilin-2 cooperates with TGFbeta-type1 receptor to promote epithelial-mesenchymal transition in colorectal cancer cells. Our results suggest a direct role of NRP2 in epithelial-mesenchymal transition and highlight a cross-talk between neuropilin-2 and TGF-beta1 signaling to promote cancer progression. These results suggest that neuropilin-2 fulfills all the criteria of a therapeutic target to disrupt multiple oncogenic functions in solid tumors.
Référence
PLoS One. 2011;6(7):e20444