Potential therapeutic targets of epithelial–mesenchymal transition in melanoma

Abstract

Melanoma is a cutaneous neoplastic growth of melanocytes with great potential to invade and metastasize, especially when not treated early and effectively. Epithelial-mesenchymal transition (EMT) is the process by which melanocytes lose their epithelial characteristics and acquire mesenchymal phenotypes. Mesenchymal protein expression increases the motility, invasiveness, and metastatic potential of melanoma. Many pathways play a role in promotion of mesenchymal protein expression including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, and several others. Downstream effectors of these pathways induce expression of EMT transcription factors including Snail, Slug, Twist, and Zeb that promote repression of epithelial and induction of mesenchymal character. Emerging research has demonstrated that a variety of small molecule inhibitors as well as phytochemicals can influence the progression of EMT and may even reverse the process, inducing re-expression of epithelial markers. Phytochemicals are of particular interest as supplementary treatment options because of their relatively low toxicities and anti-EMT properties. Modulation of EMT signaling pathways using synthetic small molecules and phytochemicals is a potential therapeutic strategy for reducing the aggressive progression of metastatic melanoma. In this review, we discuss the emerging pathways and transcription factor targets that regulate EMT and evaluate potential synthetic small molecules and naturally occurring compounds that may reduce metastatic melanoma progression.

Aberrant expression of kallikrein‐related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion

“…The mechanism by which KLK7 inhibits cell proliferation is not clear but may be due to cell cycle arrest or processing of repressive factors (cytokines) such as IL-1beta, a known substrate of KLK7 (Nylander-Lundqvist and Egelrud, 1997) that has been shown to inhibit melanoma growth (Neville et al, 1990). Accumulating evidence indicates that EMT, often accompanied by loss of E-cadherin expression, plays a critical role in metastasis, whereby the genes involved in EMT promote cell migration and invasion but suppress proliferation of melanoma (Haass and Herlyn, 2005;Pearlman et al, 2017). In pancreatic cells, KLK7 induced shedding of Ecadherin (Johnson et al, 2007) and induced EMT in prostate cancer ) associated with a remarkably increased cell migration and invasion.…”

Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting Hedgehog signaling pathway

“…More staining could be found in g-IR group, but in the CCM group and CCMCg-IR group there were fewer. b-catenin, which was reported to act as a trigger of EMT, 52,53 and translocate into nucleus in the initial stage of EMT, 14,54 was detected to have more expression in both nucleus and cytoplasm in g-IR group, but less expression in CCM group and CCMCg-IR group. This provided an convincing result that Curcumin could cover the induction of EMT which caused by g-irradiation in the protein level.…”

Canine oral primary melanoma cells exhibit shift to mesenchymal phenotype and phagocytic behaviour

“…EMT can be grossly characterized by (a) loss of typical epithelial characteristics such as apical‐basolateral polarization, basement membrane integrity and cell‐cell adhesion and (b) gain of mesenchymal features via suppression of E‐cadherin expression allowing EMT transcription factors to induce increased expression of mesenchymal proteins. The later include matrix metalloproteinases (MMPs) and Vimentin that promote ECM degradation, cell motility and invasion . In human MM, EMT‐mediated changes prevent senescence and apoptosis and enhance the migratory capacity and invasiveness of tumour cells, thus promoting the transition from MM in situ to metastatic MM .…”

“…[9][10][11][12] EMT can be grossly characterized by ( Vimentin that promote ECM degradation, cell motility and invasion. 9,13,14 In human MM, EMT-mediated changes prevent senescence and apoptosis and enhance the migratory capacity and invasiveness of tumour cells, thus promoting the transition from MM in situ to metastatic MM. 13 Moreover, tumour cells exhibiting a mesenchymal morphology have been shown to resist to chemotherapy and radiation, indicating that targeting MM-associated EMT-mediated processes might represent an expedient therapeutic approach.…”

“…9,13,14 In human MM, EMT-mediated changes prevent senescence and apoptosis and enhance the migratory capacity and invasiveness of tumour cells, thus promoting the transition from MM in situ to metastatic MM. 13 Moreover, tumour cells exhibiting a mesenchymal morphology have been shown to resist to chemotherapy and radiation, indicating that targeting MM-associated EMT-mediated processes might represent an expedient therapeutic approach. 13 Recently, the cell adhesion protein CD146 (MCAM; MUC18) has been identified as having a multifaceted role in human MM progression and metastasis.…”