期刊
ONCOTARGET
卷 6, 期 5, 页码 2779-2793出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2995
关键词
BRAF(V600E) melanoma; NRAS(Q61R) melanoma; Sema6A; Mical1; cell survival
资金
- New Idea Award (Ministero della Salute)
- Filas
- Italian Association for Cancer Research (AIRC) [SPMCO 9979]
- AIRC [IG 12020]
We used whole genome microarray analysis to identify potential candidate genes with differential expression in BRAF(V600E) vs NRAS(Q61R) melanoma cells. We selected, for comparison, a peculiar model based on melanoma clones, isolated from a single tumor characterized by mutually exclusive expression of BRAF(V600E) and NRAS(Q61R) 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 BRAF(V600E) 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 NRAS(Q61R) 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 BRAF(V600E) melanoma.
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