We are studying the role of microRNAs in development, differentiation and malignant transformation of melanocyte (melanoma). Our studies are focused on melanocytes, with the goal to develop novel approaches in the prevention, diagnosis, and treatment of skin cancer in general and melanoma in particular. In addition, we are using these systems as a model for exploring basic microRNA biogenesis.
When it escapes early detection, malignant melanoma becomes a highly lethal and treatment-refractory cancer. Melastatin is greatly downregulated in metastatic melanomas and is widely believed to function as a melanoma tumor suppressor. Here we report that tumor suppressive activity is not mediated by melastatin but instead by a microRNA (miR-211) hosted within an intron of melastatin. Increasing expression of miR-211 but not melastatin reduced migration and invasion of malignant and highly invasive human melanomas characterized by low levels of melastatin and miR-211. An unbiased network analysis of melanoma-expressed genes filtered for their roles in metastasis identified three central node genes: IGF2R, TGFBR2, and NFAT5. Expression of these genes was reduced by miR-211, and knockdown of each gene phenocopied the effects of increased miR-211 on melanoma invasiveness. These data implicate miR-211 as a suppressor of melanoma invasion whose expression is silenced or selected against via suppression of the entire melastatin locus during human melanoma progression.
Modulating miR-211 dramatically reduces melanoma motility.
Real-time video microscopy of human primary melanoma treated with control mimic (A) or miRNA-211 mimic (B).
TDICER is a central regulator of microRNA maturation. However, little is known about mechanisms regulating its expression in development or disease. While profiling miRNA expression in differentiating melanocytes, two populations were observed: some upregulated at the pre-miRNA stage, and others upregulated as mature miRNAs (with stable pre-miRNA levels). Conversion of pre-miRNAs to fully processed miRNAs appeared to be dependent upon stimulation of DICER expression—an event found to occur via direct transcriptional targeting of DICER by the melanocyte master transcriptional regulator MITF. MITF binds and activates a conserved regulatory element upstream of DICER’s transcriptional start site upon melanocyte differentiation. Targeted KO of DICER is lethal to melanocytes, at least partly via DICER-dependent processing of the pre-miRNA-17~92 cluster thus targeting BIM, a known proapoptotic regulator of melanocyte survival. These observations highlight a central mechanism underlying lineage-specific miRNA regulation which could exist for other cell types during development.
Seeking PhD/MSc/Postdoctoral candidate for research project:
We are studying the role of microRNAs in development, differentiation and malignant transformation of melanocyte (melanoma). Our studies is focused on melanocytes, with the goal to develop novel approaches in the prevention, diagnosis, and treatment of skin cancer in general and melanoma in particular. In addition, we are using these systems a model for exploring basic microRNA biogenesis.