Fig. 1

Signalling pathways involved in CM, UM and MM oncogenesis, and regulation of HIF under hypoxia. The G protein-coupled receptor (GPCR) and its Gα subunits GNAQ and GNA11, downstream activate MEK1/2. The C-X-C chemokine receptor 4 (CXCR4) and c-Met activate the mitogen-activated protein kinase (MAPK) signalling pathway, consisting of BRAF-MEK1/2-ERK1/2. The KIT receptor activates the PI3K/Akt/mTOR pathway, which is influenced by phosphatase and tensin homolog (PTEN), inhibiting  p53. Loss of NF1 in melanoma promotes transition of RAS/GDP (inactive state) to its active state NRAS/GTP, in turn activating the BRAF-MEK1/2-ERK1/2 and PI3K/Akt/mTOR pathways. All of these pathways promote HIF-1α and HIF-2α synthesis and activity. Hypoxia drives HIF-1α and HIF-2α stabilization into the nucleus, with consequent induction of several genes involved in angiogenesis, survival, metastasization, EMT, drug resistance, vasculogenic mimicry through p300/CBP binding to HRE