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 (miRs) are small endogenous non-coding RNAs able to post-transcriptionally down-regulate the expression of direct target genes. Using a melanoma progression model, miR-146a was identified as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth while it suppresses dissemination. It was determined that miR-146a coordinated melanoma cell growth by its direct targets lunatic fringe (LFNG) and NUMB which operate on the NOTCH/PTEN/Akt pathway; while, inhibition of metastasis formation was linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlated with melanoma recurrence and was enriched in both patients-derived melanoma and cutaneous metastasis specimens, while its direct targets were depleted. However, miR-146a levels drop in Circulating Tumor Cells (CTCs), suggesting the necessity for miR-146 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.

IMPLICATIONS: miR-146a controls melanoma progression in a dual-way, promoting growth and inhibiting dissemination; however, it is poorly expressed in CTCs, resulting in overall tumor spreading and distant-site colonization.