Abstract
It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNAs specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 is likely to be involved in migration and metastasis of melanoma cells. We carried out a microarray-based gene expression profiling using a Sox10-specific siRNA to identify relevant regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1r) partake in the regulation of migration. We provide evidences that the effect of Sox10 on migration is mediated in large part by Mitf, a transcription factor downstream to Sox10. Among the mouse melanoma cell lines examined, however, only B16F10 showed robust down-regulation of Sox10 and inhibition of cell migration indicating that further dissection of dosage effects and/or cell line-specific regulatory networks is necessary. The involvement of Mc1r in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represents potential targets of therapeutic intervention.
Highlights
Melanocytes originate from the neural crest cells during embryonic development [1,2]
We first sought to determine if Sox10 is involved in regulating migratory behavior of B16F10 melanoma cells
The notion that key genes in development and differentiation of melanocytes are involved in metastasis of melanoma strongly suggests that elaboration of molecular function of such genes would reveal much about the mechanism of metastasis [4]
Summary
Melanocytes originate from the neural crest cells during embryonic development [1,2]. Like other cell types from the same lineage, developing melanocytes undergo an extensive migration prior to fully differentiating into pigment producing cells of epidermis and hair follicles. Weinberg and co-workers compared the metastatic behavior of melanocytes, fibroblasts, and epithelial cells after introducing identical set of transforming genes to each cell type and found that melanocytes attain metastatic characteristics by far the most efficiently [4]. This implies that a set of lineage specific factors expressed in melanocytes but not in others are at least partly attributable for the metastatic proclivity of this cell type
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