Searching for the 'melano-miRs': miR-214 drives melanoma metastasis.

Since the beginning of micro-RNA (miR) research, several attempts have been made to identify the ‘melano-miRs’, which are involved in melanoma progression. Indeed, a small number of miRs have been identified to regulate some genes involved in melanogenesis. However, the miRs that control the pathway to the malignant phenotype are yet undescribed. In this issue of the EMBO Journal, Penna et al (2011) demonstrate that miR-214 is overexpressed in metastatic melanoma cell lines and tumour specimens. miR-214 regulates the expression of two transcription factors AP-2c (directly) and AP-2a (indirectly). These transcription factors, particularly AP-2a, have been previously shown to play major roles in melanoma metastasis via regulation of genes involved in extravasation, invasion and angiogenesis. As such, this study has identified miR214 as a driver of melanoma metastasis. Limited data are available about the changes in miRNA expression levels in malignant melanoma. This investigative effort began in 2008 with the first report by Bemis et al (2008), linking the expression of a single mir, miR-137, with the expression of MITF, a ‘master regulator’ of melanogenesis. MITF, however, has since been shown to be also regulated by miR-182 (Segura et al, 2009). Overexpression of miR-182 was associated with increased survival and invasive properties of melanoma cells via regulation of both MITF and FOX03. miR-182 was found to enhance the invasive capability of melanoma cells in vitro and increase their metastatic potential in vivo in an experimental lung metastasis model. However, these studies never identified the ‘metastatic’ target genes involved in this process. Other miRNAs with known target genes in melanoma are miR-221 and miR-222, which regulate the expression of both p27 and in particular c-KIT, which is downregulated in metastatic melanoma cells. The c-KIT gene is regulated mainly by the AP-2a transcription factor (vide infra). Moreover, treatment with antagomiRs against miR-221/222 inhibited melanoma proliferation and invasion in vitro and melanoma growth in vivo (Felicetti et al, 2008). The first discovered miR to be involved in cancer formation was miRNA let-7. The family of miRs let 7a and let 7b were later reported to play a role in melanoma tumourigenesis. For example, let 7b acts as a negative regulator of melanoma cell proliferation via regulation of cyclin D1, whereas let 7a was demonstrated to regulate the expression of integrin-b3 and the Ras Oncogene (reviewed in Mueller and Bosserhoff, 2009). All of the above studies focused on single miRs and their individual roles in melanoma progression. Other attempts have been made to identify a cluster of miRs that are either involved in melanogenesis or predictors of survival. For example, Ozsolak et al (2008) searched for miRs that are specific to melanoma progression. To that end, they screened for miRs that are specifically regulated by MITF and identified