Sema6A and Mical1 control cell growth and survival of BRAFV600E human melanoma cells

Rossella Loria, Giulia Bon, Valentina Perotti, Enzo Gallo, Ilaria Bersani, Paola Baldassari, Manuela Porru, Carlo Leonetti, Selene Di Carlo, Paolo Visca, Maria Felice Brizzi, Andrea Anichini, Roberta Mortarini, Rita Falcioni

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2763-2777
Number of pages15
JournalOncotarget
Volume6
Issue number5
Publication statusPublished - 2015

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Keywords

  • BRAF melanoma
  • Cell survival
  • Mical1
  • NRAS melanoma
  • Sema6A

ASJC Scopus subject areas

  • Oncology

Cite this

Loria, R., Bon, G., Perotti, V., Gallo, E., Bersani, I., Baldassari, P., Porru, M., Leonetti, C., Carlo, S. D., Visca, P., Brizzi, M. F., Anichini, A., Mortarini, R., & Falcioni, R. (2015). Sema6A and Mical1 control cell growth and survival of BRAFV600E human melanoma cells. Oncotarget, 6(5), 2763-2777.