Role of miRNAs in Melanoma Metastasis

Abstract

Tumour metastasis is a multistep process. Melanoma is a highly aggressive cancer and metastasis accounts for the majority of patient deaths. microRNAs (miRNAs) are non-coding RNAs that affect the expression of their target genes. When aberrantly expressed they contribute to the development of melanoma. While miRNAs can act locally in the cell where they are synthesized, they can also influence the phenotype of neighboring melanoma cells or execute their function in the direct tumour microenvironment by modulating ECM (extracellular matrix) and the activity of fibroblasts, endothelial cells, and immune cells. miRNAs are involved in all stages of melanoma metastasis, including intravasation into the lumina of vessels, survival during circulation in cardiovascular or lymphatic systems, extravasation, and formation of the pre-metastatic niche in distant organs. miRNAs contribute to metabolic alterations that provide a selective advantage during melanoma progression. They play an important role in the development of drug resistance, including resistance to targeted therapies and immunotherapies. Distinct profiles of miRNA expression are detected at each step of melanoma development. Since miRNAs can be detected in liquid biopsies, they are considered biomarkers of early disease stages or response to treatment. This review summarizes recent findings regarding the role of miRNAs in melanoma metastasis.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…Analysis of whole-exome sequencing data revealed only a few mutations previously identified as associated with acquired resistance to targeted drugs. It is in line with the current view that in parallel to genetic alterations, melanoma cell-autonomous mechanisms of resistance can rely on complex transcriptomic adaptations supported by epigenetic regulations, including miRNA-mediated mechanisms, and extended by the interplay between tumor and stromal cells that involves cell-cell interactions, paracrine stimulation and extracellular vesicles to create a resistance-permissive niche [39][40][41][42][43][44][45][46]. Mechanisms of resistance primarily directed to support proliferation and survival of cancer cells implicate a plethora of transcriptional regulators, adaptive responses, and feedback loops that extensively affect melanoma cell phenotype enabling the expansion of distinct cell subpopulations in the presence of drug(s) [27,[47][48][49][50][51][52].…”

Inhibitors of HSP90 in melanoma

“…In addition, a loss of functional PTEN (phosphatase and tensin homolog) and enhanced activity of the PI3K (phosphatidylinositol 3-kinase)/AKT/ mTOR (mechanistic target of rapamycin kinase) pathway, a suppression of BIM (BCL-2 interacting mediator of cell death), a loss of STAG2 (stromal antigen 2) or STAG3 (stromal antigen 3) that are the subunits of cohesion complex, an increase in cyclin D1 level, enhanced expression of several microRNAs, and expression of resistance-associated genes including AXL, PDGFRB (platelet-derived growth factor receptor beta) and EGFR (epidermal growth factor receptor) have been demonstrated to contribute to resistance of melanoma cells. In addition to cell-intrinsic mechanisms, growth factors derived from stromal cells and hypoxia can modulate melanoma cell sensitivity to targeted drugs [10][11][12][14][15][16], and long-term therapy with BRAF V600E inhibitor can develop resistance to other drugs including dacarbazine [17]. Resistance to immunotherapy can also emerge, and melanoma cells resistant to PD-1 inhibitors show upregulation of receptors VISTA (V-domain Ig suppressor of T cell activation) and TIM-3 (T-cell immunoglobulin and mucin domain-containing…”

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

“…Many studies revealed that the expression of several miRNAs is deregulated in melanoma cells and that aberrant miRNA expression is undoubtedly linked to important processes affecting tumor formation and progression [35,36,[84][85][86][87][88][89][90][91]. One example are members of the let-7 miRNA family which are involved in melanoma invasiveness [92], cell cycle promotion [93] and metabolism [94].…”

“…Further risk factors for melanoma development are family predisposition [80] as well as multiple occurrences of melanocytic nevi (which are benign proliferations of melanocytes in the skin and can be transformed to precursor lesions of melanoma) [81]. In advanced/metastatic disease, systemic first-line therapeutic options are specific BRAF-inhibitors for BRAF V600E -mutated melanomas [82] as well as immune checkpoint inhibitors [83] but the understanding of emergence of acquired resistance to these therapies is still an unmet clinical need.Many studies revealed that the expression of several miRNAs is deregulated in melanoma cells and that aberrant miRNA expression is undoubtedly linked to important processes affecting tumor formation and progression [35,36,[84][85][86][87][88][89][90][91]. One example are members of the let-7 miRNA family which are involved in melanoma invasiveness [92], cell cycle promotion [93] and metabolism [94].…”