Fig. 2
From: Therapeutic implications of cellular and molecular biology of cancer stem cells in melanoma
Signaling involved in CSCs that mediates melanoma progression. Hedgehog signaling transcriptionally regulates E2F1 expression and promotes iASPP expression leading to melanoma progression. BRAF (V600E) and NRAS (Q61K) signaling induce miR-146a through MYC. This miRNA enhances the Notch signaling through downregulation of NUMB expression. Notch1 Intracellular Cleaved Domain (NICD1) translocates into the nucleus and transcriptionally regulates the expression of CD133 that preferentially activates the p-38 MAPK pathway-mediated AP-1-DNA binding. Additionally, AP-1-DNA binding also induced by Wnt signaling leading to higher melanoma metastasis and angiogenesis. IGF binds to their receptor (IGF1R) and activates the phosphorylation of ERK and p38 that leads to HIF1α-DNA binding and maintain melanoma stem-like phenotype. Selected EMT modulator such as TGFβ activates PI3K-Akt signaling pathway and induces amoeboidal cell migration and EMT phenotype in melanoma. iASPP: inhibitor of apoptosis-stimulating protein of p53; NICD1: notch1 intracellular cleaved domain; MAPK: mitogen-activated protein kinases; IGF1R: insulin growth factor receptor 1; IGFBP5: insulin growth factor binding protein 5; HIF: hypoxia-inducible factor; TGFβ: transforming growth factor beta; EMT: epithelial to mesenchymal transition