title: The Proprotein Convertase Furin Contributes to Rhabdomyosarcoma Malignancy by Promoting Vascularization, Migration and Invasion.
abstract: The proprotein convertase (PC) furin cleaves precursor proteins, an important step in the activation of many cancer-associated proteins. Substrates of furin and furin-like PCs play a role in proliferation, metastasis and invasion. Some of them are involved in the progression of the pediatric soft tissue sarcoma rhabdomyosarcoma (RMS). In this study, we show that PCs, and in particular furin, are expressed in RMS cell lines. To investigate the functional role of furin, we generated RMS cell lines with modulated furin activity. Silencing or stable inhibition of furin delayed tumor growth in Rh30 and RD xenografts in vivo, and was correlated with lower microvessel density. Reduced furin activity also decreased migration and invasion abilities in vitro, and inhibition of furin in RMS cells diminished processing of IGF1R, VEGF-C, PDGF-B and MT1-MMP, leading to lower levels of mature proteins. Furthermore, we found that furin activity is required for proper IGF signaling in RMS cells, as furin silencing resulted in reduced phosphorylation of Akt upon IGF1 stimulation. Taken together, our results suggest that furin plays an important role in the malignant phenotype of RMS cells by activating proteins involved in tumor growth and vascularization, metastasis and invasion.
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Jaaks
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Alessandro
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Grob
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Sina
authors.initials: S
authors.lastname: Büel
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Katarina
authors.initials: K
authors.lastname: Hajdin
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat W
authors.initials: BW
authors.lastname: Schäfer
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.|Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Bernasconi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D045683:Furin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C583557:IGF1 protein, human; C000597236:IGF1R protein, human; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D017451:Receptors, Somatomedin; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C468731:FURIN protein, human; D045683:Furin; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14