Expression of mutated BRAF (V600E) in melanocytes activates metabotropic glutamate receptor 1 expression

Melanoma is the most aggressive form of skin cancer, which is caused by the neoplastic transformation of melanocytes. The precise genetic aberrations that initiate the transformation process remain largely unknown. Several genetic mutations have shown to be critical in maintaining the transformed phenotypes and the temporal expression of these mutated proteins is also vital on the onset of dysregulated cell growth. The current study is to explore a relationship between two genetic aberrations, both have been shown to play a role in melanoma development. Our group has identified the ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (Grm1) in melanocytes was sufficient to induce spontaneous metastatic melanoma development in vivo by the establishment of two transgenic mouse models (TG-3 and Epv). Mutated BRAF at residues 600 was shown in about 60% of nevi and melanoma specimens. Mouse models with mutated BRAF alone led to hyper-proliferated melanocytes in the absence of tumor development. Unexpectedly, we detected Grm1 expression in tumor samples harboring mutated B-RAF(V600E) mutation on PTEN null background by immunohistochemical staining. We hypothesize that one of the consequences of mutated BRAFis activation of Grm1 expression. We took advantage of an inducible BRAFmouse model, BJB, which has an inducible BRAF mutation (V600E) genotype only in melanocytes. We observed hyperpigmentation on their ears, tails, and skin samples, Grm1 expression was also detected. There was no tumor formation even after 13 months, while Grm1 expression persisted. We hypothesize that the order of the expression of mutated BRAF and Grm1 must play a role in the onset of melanocytic transformation. In in vitro cumltured cell experiments, we also detected Grm1 expression after introduction of mutated BRAF into immortalized non-tumorigenic mouse melanocytes, MelanA cells. Moreover, siRNA decrease in mutated BRAF expression by silencing RNA resulted in parallel reduction in Grm1 expression. Taken together, these results point to an association between mutated BRAF and Grm1 expression in vivo and in vitro.M.S.Includes bibliographical referencesby Ho-Chung Che