TY - JOUR
T1 - Myoferlin plays a key role in VEGFA secretion and impacts tumor-associated angiogenesis in human pancreas cancer
AU - Fahmy, Karim
AU - Gonzalez, Arnaud
AU - Arafa, Mohammad
AU - Peixoto, Paul
AU - Bellahcène, Akeila
AU - Turtoi, Andrei
AU - Delvenne, Philippe
AU - Thiry, Marc
AU - Castronovo, Vincent
AU - Peulen, Olivier
N1 - © 2015 UICC.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
KW - Adenocarcinoma/blood supply
KW - Calcium-Binding Proteins/analysis
KW - Carcinoma, Pancreatic Ductal/blood supply
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Humans
KW - Membrane Proteins/analysis
KW - Muscle Proteins/analysis
KW - Neovascularization, Pathologic/etiology
KW - Pancreatic Neoplasms/blood supply
KW - Platelet Endothelial Cell Adhesion Molecule-1/analysis
KW - Vascular Endothelial Growth Factor A/analysis
U2 - 10.1002/ijc.29820
DO - 10.1002/ijc.29820
M3 - Article
C2 - 26311411
SN - 0020-7136
VL - 138
SP - 652
EP - 663
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 3
ER -