Figure 2.

The interplay of non-coding RNAs with the melanoma microenvironment: (A) Melanoma cells overcome oxygen deprivation. Downregulation of miR-211 elevates PDK4 (pyruvate dehydrogenase kinase 4) levels, leading to the inhibition of PDH (pyruvate dehydrogenase) via phosphorylation, which in turn limits oxidative phosphorylation as pyruvate is rerouted away from the TCA (tricarboxylic acid cycle). Increased levels of HIF1α (hypoxia-inducible factor 1 alpha) lead to the upregulation of several miRNAs that target BNIP3 (BCL2/adenovirus E1B interacting protein 3), stimulating glutamine metabolism; (B) MicroRNAs promote neo-angiogenesis. Certain miRNAs are upregulated in melanoma cells and distributed to endothelial cells via exosomes, in order to increase the migratory and pro-angiogenic potential of said cells and recruit them to the MME, found either in the cutaneous tissue or in lymph nodes; (C) Malignant melanocytes reprogramme immune cells to favour the establishment of an immunosuppressive microenvironment. In principle, miRNAs (often transported via exosomes) recruit and promote the expansion of MDSCs (myeloid-derived suppressor cells) and T-regs (regulatory T cells), inhibit cytotoxic T cells and trick NK (natural killer) cells by shedding soluble ligands in order to avoid tumour cell lysis. The role of HOTAIR in this case is uncertain, even though its overexpression was observed in the plasma membrane of lymphocytes associated with the MME; (D) Melanoma-derived melanosomes deliver miR-211 to normal fibroblasts, which inhibits the expression of IGFR2 (insulin-like growth factor receptor 2) and activates MAPK signalling, to transform them into cancer-associated fibroblasts (CAF) and prepare the dermis for future invasion. ApoE: Apolipoprotein E; PDGF-C: Platelet-derived growth factor C; VEGF-C: Vascular endothelial growth factor C; NKG2D: natural killer group 2, member D; ULBP2: UL16 binding protein 2. Figure created with BioRender.com.