Aberrant Silencing of a Large Micro-RNA Cluster on Chromosome 14q32 and its Relation to Aberrant c-MET/n-RAS Signaling in Cutaneous Malignant Melanoma-Implications for Novel Therapeutic Approaches and Biomarkers
The incidence of melanoma is increasing worldwide, and when melanoma metastasizes, it is rarely curable. Albeit significant progress in recent years, there is still urgent need for novel therapeutic targets and approaches in melanoma, especially in non-B-RAF mutated genetic subtypes. The MDACC group recently showed that wild type, N-RAS-mutated and B-RAF-mutated varied in their clinicopathological characteristics, and that the two former were more strongly associated with activation of the c-Met pathway, rendering these tumors more susceptible to c-Met inhibition than B-RAF-mutated tumors. The Sheba group recently showed that a large tumor-suppressor miRNA cluster on chromosome 14q32 was significantly down-regulated in melanoma cell lines and samples by epigenetic mechanisms, and that stepwise transformation of normal melanocytes led to a gradual decrease in the expression of miRNAs from this cluster. The temporal and causal relationship between 14q32-miRNA cluster silencing, c-Met activation and the tumorigenic/metastatic behavior of melanocytes is currently unknown.