title: Myoferlin plays a key role in VEGFA secretion and impacts tumor-associated angiogenesis in human pancreas cancer.
abstract: Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas adenocarcinoma where its expression was associated to a bad prognosis. However, the function of myoferlin in pancreas adenocarcinoma has not been reported. In other cell types, myoferlin is involved in several key plasma membrane processes such as fusion, repair, endocytosis and tyrosine kinase receptor activity. In this study, we showed that myoferlin silencing in BxPC-3 human pancreatic cancer cells resulted in the inhibition of cell proliferation in vitro and in a significant reduction of the tumor volume in chick chorioallantoic membrane assay. In addition to be smaller, the tumors formed by the myoferlin-silenced cells showed a marked absence of functional blood vessels. We further demonstrated that this effect was due, at least in part, to an inhibition of VEGFA secretion by BxPC-3 myoferlin-silenced cells. Using immunofluorescence and electron microscopy, we linked the decreased VEGFA secretion to an impairment of VEGFA exocytosis. The clinical relevance of our results was further strengthened by a significant correlation between myoferlin expression in a series of human pancreatic malignant lesions and their angiogenic status evaluated by the determination of the blood vessel density.
authors: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Karim
authors: K
authors: Fahmy
authors: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Arnaud
authors: A
authors: Gonzalez
authors: Department of Pathology, Faculty of Medicine, University of Mansoura, Mansoura, Egypt.
authors: Mohammad
authors: M
authors: Arafa
authors: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Paul
authors: P
authors: Peixoto
authors: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Akeila
authors: A
authors: Bellahcène
authors: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Andrei
authors: A
authors: Turtoi
authors: Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Philippe
authors: P
authors: Delvenne
authors: Laboratory of Cell Biology, GIGA-R, University of Liege, Liege, Belgium.
authors: Marc
authors: M
authors: Thiry
authors: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Vincent
authors: V
authors: Castronovo
authors: Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium.
authors: Olivier
authors: O
authors: Peulen
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000502:physiology*; D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology*; D009124:Muscle Proteins / Q000032:analysis / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000209:etiology*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; C415584:MYOF protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: VEGF; angiogenesis; exocytosis; myoferlin; pancreas ductal adenocarcinoma