Consensus of Melanoma Gene Expression Subtypes Converges on Biological EntitiesIdentification of recurrent mutation in the BRAF oncogene in melanoma has led to the development of highly selective kinase inhibitors (Larkin et al., 2014). Although dramatic treatment responses are initially observed, responses are rarely durable. The mutational classification based on BRAF, NRAS, and NF1 mutations that has been established, however, is nonoverlapping with classification derived from gene expression profiling (The Cancer Genome Atlas Network [TCGA], 2015; Jönsson et al., 2010).
Regulation of Melanoma Progression through the TCF4/miR-125b/NEDD9 CascadeMelanoma progression from a primary lesion to a distant metastasis is a complex process associated with genetic alterations, epigenetic modifications, and phenotypic switches. Elucidation of these phenomena may indicate how to interfere with this fatal disease. The role of microRNAs as key negative regulators of gene expression, controlling all cellular processes including cell migration and invasion, is now being recognized. Here, we used in silico analysis of microRNA expression profiles of primary and metastatic melanomas and functional experiments to show that microRNA-125b (miR-125b) is a determinant candidate of melanoma progression: (i) miR-125b is more strongly expressed in aggressive metastatic than primary melanomas, (ii) there is an inverse correlation between the amount of miR-125b and overall patient survival, (iii) invasion/migration potentials in vitro are inversely correlated with the amount of miR-125b in a series of human melanoma cell lines, and (iv) inhibition of miR-125b reduces migratory and invasive potentials without affecting cell proliferation in vitro.
Secreted Frizzled-Related Protein 2 (sFRP2) Functions as a Melanogenic Stimulator; the Role of sFRP2 in UV-Induced Hyperpigmentary DisordersIn this study, we found that secreted frizzled-related protein 2 (sFRP2) is overexpressed in the hyperpigmentary skin of melasma and solar lentigo and in acutely UV-irradiated skin. To investigate the effect of sFRP2 on melanogenesis, normal human melanocytes were infected with sFRP2-lentivirus or sh-sFRP2. It was found that sFRP2 stimulates melanogenesis through microphthalmia-associated transcription factor and/or tyrosinase upregulation via β-catenin signaling. The stimulatory action of sFRP2 in pigmentation was further confirmed in melanocytes cocultured with fibroblasts and in ex vivo cultured skin.