Dbl oncogene expression in MCF-10 A epithelial cells disrupts mammary acinar architecture, induces EMT and angiogenic factor secretion.
The proteins of the Dbl family are guanine nucleotide exchange factors (GEFs) of Rho GTPases and are known to be involved in cell growth regulation. Alterations of the normal function of these proteins lead to pathological processes such as developmental disorders, neoplastic transformation, and tumor metastasis. We have previously demonstrated that expression of Dbl oncogene in lens epithelial cells modulates genes encoding proteins involved in epithelial-mesenchymal-transition (EMT) and induces angiogenesis in the lens. Our present study was undertaken to investigate the role of Dbl oncogene in epithelial cells transformation, providing new insights into carcinoma progression.To assess how Dbl oncogene can modulate EMT, cell migration, morphogenesis, and expression of pro-apoptotic and angiogenic factors we utilized bi- and 3-dimensional cultures of MCF-10 A cells. We show that upon Dbl expression MCF-10 A cells undergo EMT. In addition, we found that Dbl overexpression sustains Cdc42 and Rac activation inducing morphological alterations, characterized by the presence of lamellipodia and conferring a high migratory capacity to the cells. Moreover, Dbl expressing MCF-10 A cells form altered 3D structures and can induce angiogenesis by producing proangiogenic factors such as CCL2. These results support a role for Dbl oncogene in epithelial cell differentiation and transformation and suggest the relevance of GEF deregulation in tumor onset and progression.
a Laboratory of Molecular Biology ; Istituto Giannina Gaslini ; Genova , Italy.
Cristina
C
Vanni
Marzia
M
Ognibene
Federica
F
Finetti
Patrizia
P
Mancini
Sara
S
Cabodi
Daniela
D
Segalerba
Maria Rosaria
MR
Torrisi
Sandra
S
Donnini
Maria Carla
MC
Bosco
Luigi
L
Varesio
Alessandra
A
Eva
D061354:Acinar Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D042501:Angiogenic Proteins / Q000378:metabolism*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D042361:Mammary Glands, Human / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D042501:Angiogenic Proteins; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D020662:Guanine Nucleotide Exchange Factors; C057811:MCF2 protein, human; D011518:Proto-Oncogene Proteins; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins
CCL2; Dbl oncogene; EMT; EMT, Epithelial-mesenchymal-transition; MCF-10 A; angiogenesis; migration; α-SMA, α-smooth muscle actin