Sema6A and Mical1 control cell growth and survival of BRAFV600E human melanoma cells
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Rossella Loria1, Giulia Bon1, Valentina Perotti2, Enzo Gallo3, Ilaria Bersani2, Paola Baldassari2, Manuela Porru4, Carlo Leonetti4, Selene Di Carlo1, Paolo Visca3, Maria Felice Brizzi5, Andrea Anichini2, Roberta Mortarini2 and Rita Falcioni1
1 Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy
2 Human Tumors Immunobiology Unit, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3 Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy
4 Department of Chemotherapy, Regina Elena National Cancer Institute, Rome, Italy
5 Department of Medical Sciences, University of Turin, Turin, Italy
Rita Falcioni, email:
Roberta Mortarini, email:
Keywords: BRAFV600E melanoma, NRASQ61R melanoma, Sema6A, Mical1, cell survival
Received: August 28, 2014 Accepted: December 12, 2014 Published: December 18, 2014
We used whole genome microarray analysis to identify potential candidate genes with differential expression in BRAFV600E vs NRASQ61R melanoma cells. We selected, for comparison, a peculiar model based on melanoma clones, isolated from a single tumor characterized by mutually exclusive expression of BRAFV600E and NRASQ61R in different cells. This effort led us to identify two genes, SEMA6A and MICAL1, highly expressed in BRAF-mutant vs NRAS-mutant clones. Real-time PCR, Western blot and immunohistochemistry confirmed preferential expression of Sema6A and Mical1 in BRAFV600E melanoma. Sema6A is a member of the semaphorin family, and it complexes with the plexins to regulate actin cytoskeleton, motility and cell proliferation. Silencing of Sema6A in BRAF-mutant cells caused cytoskeletal remodeling, and loss of stress fibers, that in turn induced cell death. Furthermore, Sema6A depletion caused loss of anchorage-independent growth, inhibition of chemotaxis and invasion. Forced Sema6A overexpression, in NRASQ61R clones, induced anchorage-independent growth, and a significant increase of invasiveness. Mical1, that links Sema/PlexinA signaling, is also a negative regulator of apoptosis. Indeed, Mical-1 depletion in BRAF mutant cells restored MST-1-dependent NDR phosphorylation and promoted a rapid and massive NDR-dependent apoptosis. Overall, our data suggest that Sema6A and Mical1 may represent new potential therapeutic targets in BRAFV600E melanoma.
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