Status of RASSF1A in uveal melanocytes and melanoma cells
Molecular Cancer Research. 2011-07-25; 9(9): 1187-1198
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1. Mol Cancer Res. 2011 Sep;9(9):1187-98. doi: 10.1158/1541-7786.MCR-10-0437. Epub
2011 Jul 25.
Status of RASSF1A in uveal melanocytes and melanoma cells.
Calipel A(1), Abonnet V, Nicole O, Mascarelli F, Coupland SE, Damato B, Mouriaux
(1)Service Universitaire d’Ophtalmologie, Universitede Caen Basse-Normandie,
Universite Paris-Descartes, CEA, CNRS, Centre CYCERON, Bd Henri Becquerel,
BP5229, 14074 Caen cedex, France.
RASSF1A gene, found at the 3p21.3 locus, is a tumor suppressor gene frequently
hypermethylated in human cancers. In this study, we report that compared with
melanocytes in normal choroid, RASSF1A is downregulated in uveal melanoma samples
and in uveal melanoma cell lines. LOH at 3p21.3 was detected in 50% of uveal
melanoma. Moreover, methylation of the RASSF1A promoter was detected in 35 of 42
tumors (83%) and RASSF1A was also weakly expressed at the mRNA level. These data
indicate that LOH at the RASSF1A locus or RASSF1A promoter methylation may partly
account for the suppression of RASSF1A expression observed in uveal melanoma.
Furthermore, following ectopic expression in three RASSF1A-deficient melanoma
cell lines (OCM-1, Mel270, and 92.1), RASSF1A weakly reduces cell proliferation
and anchorage-independent growth of uveal melanoma cells without effect on ERK1/2
activation, cyclin D1 and p27(Kip1) expression. This study explored biological
functions and underlying mechanisms of RASSF1A in the ERK1/2 pathway in normal
uveal melanocytes. We showed that siRNA-mediated depletion of RASSF1A increased
ERK1/2 activation, cyclin D1 expression, and also decreased p27(Kip1) expression
in normal uveal melanocytes. Moreover, that the depletion of RASSF1A induced
senescence-associated β-galactosidase activity and increased p21(Cip1) expression
suggests that RASSF1A plays a role in the escape of cellular senescence in normal
uveal melanocytes. Interestingly, we found that RASSF1A was epigenetically
inactivated in long-term culture of uveal melanocytes. Taken together, these data
show that depletion of RASSF1A could be an early event observed during senescence
of normal uveal melanocytes and that additional alterations are acquired during
malignant transformation to uveal melanoma.
PMID: 21788308 [Indexed for MEDLINE]