title: Neuropilin-2 expression promotes TGF-β1-mediated epithelial to mesenchymal transition in colorectal cancer cells.
abstract: 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-β1. The expression of neuropilin-2 on colon cancer cell lines was indeed shown to promote transforming-growth factor-β1 signaling, leading to a constitutive phosphorylation of the Smad2/3 complex. Treatment with specific TGFβ-type1 receptor kinase inhibitors restored E-cadherin levels and inhibited in part neuropilin-2-induced vimentin expression, suggesting that neuropilin-2 cooperates with TGFβ-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-β1 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.
authors: INSERM UMR 645, Besançon, France.
authors: Camille
authors: C
authors: Grandclement
authors: Jean René
authors: JR
authors: Pallandre
authors: Séverine
authors: S
authors: Valmary Degano
authors: Erika
authors: E
authors: Viel
authors: Adeline
authors: A
authors: Bouard
authors: Jérémy
authors: J
authors: Balland
authors: Jean-Paul
authors: JP
authors: Rémy-Martin
authors: Benoit
authors: B
authors: Simon
authors: Alain
authors: A
authors: Rouleau
authors: Wilfrid
authors: W
authors: Boireau
authors: Michael
authors: M
authors: Klagsbrun
authors: Christophe
authors: C
authors: Ferrand
authors: Christophe
authors: C
authors: Borg
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D039943:Neuropilin-2 / Q000172:deficiency / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D039943:Neuropilin-2; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1