miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization.

Malignant melanoma is the most aggressive form of skin cancer therefore it is crucial to disclose its underlying molecular mechanisms. MicroRNAs are small endogenous non-coding RNAs able to post-transcriptionally down-regulate the expression of direct target genes. Using a melanoma progression model, we identified miR-146a as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth while it suppresses dissemination. We evidenced that melanoma cell growth is coordinated by its direct target lunatic fringe (LFNG) which operates on the NOTCH/PTEN/Akt pathway. Instead, metastasis formation inhibition is linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlates with melanoma recurrence and it is enriched both in patients-derived melanoma and cutaneous metastasis samples, while its direct targets are depleted. However, miR-146a levels drop in Circulating Tumor Cells, suggesting the necessity for miR-146a expression to fluctuate during tumor progression in order to favor tumor growth and allow dissemination. This study reconciles the contradictory biological functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions. To identify microRNAs involved in malignant melanoma progression, miR profilings have been performed in our lab taking advantage of a human melanoma cellular model consisting of a poorly aggressive B-RAF V600E-mutated parental cell line (A375P) and its four variants MA-1, MC-1, MA-2 and MC-2, derived from one (MA-1 and MC-1) or two (MA-2 and MC-2) subsequent rounds of injections in mice and showing progressively increased metastatic potential.