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Review
, 19 (12)

HGF/c-MET Signaling in Melanocytes and Melanoma

Affiliations
Review

HGF/c-MET Signaling in Melanocytes and Melanoma

Malgorzata Czyz. Int J Mol Sci.

Abstract

Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-MET) signaling is involved in complex cellular programs that are important for embryonic development and tissue regeneration, but its activity is also utilized by cancer cells during tumor progression. HGF and c-MET usually mediate heterotypic cell⁻cell interactions, such as epithelial⁻mesenchymal, including tumor⁻stroma interactions. In the skin, dermal fibroblasts are the main source of HGF. The presence of c-MET on keratinocytes is crucial for wound healing in the skin. HGF is not released by normal melanocytes, but as melanocytes express c-MET, they are receptive to HGF, which protects them from apoptosis and stimulates their proliferation and motility. Dissimilar to melanocytes, melanoma cells not only express c-MET, but also release HGF, thus activating c-MET in an autocrine manner. Stimulation of the HGF/c-MET pathways contributes to several processes that are crucial for melanoma development, such as proliferation, survival, motility, and invasiveness, including distant metastatic niche formation. HGF might be a factor in the innate and acquired resistance of melanoma to oncoprotein-targeted drugs. It is not entirely clear whether elevated serum HGF level is associated with low progression-free survival and overall survival after treatment with targeted therapies. This review focuses on the role of HGF/c-MET signaling in melanoma with some introductory information on its function in skin and melanocytes.

Keywords: HGF; MET; drug resistance; invasive growth; melanocytes; melanoma; skin; tumor microenvironment; wound healing.

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
HGF/c-MET signaling. Hepatocyte growth factor (HGF) is mainly produced and secreted by mesenchymal cells as an inactive precursor, pro-HGF. Cleavage of pro-HGF to active HGF, followed by its binding to c-MET on epithelial cells, results in the dimerization of two c-MET molecules, and structural changes in a multi-substrate docking site. Recruitment of GRB2 to this site induces the autophosphorylation and binding of various transducers. Son of Sevenless (SOS) can recruit RAS-GTP to the membrane and active RAS-GTP can trigger the MAPK/ERK pathway. The autophosphorylated residue of c-MET acts also as a docking site for PI3K, which activates the AKT/mTOR pathway. Pathway activation drives transcriptional programs that mediate a plethora of cell phenotypes, including these participating in morphogenesis, proliferation, survival, motility, and invasiveness. The MET-triggered MAPK/ERK pathway is primarily involved in cell proliferation, whereas PI3K recruitment is required for the survival and induction of cell motility and invasion. RAC1-PAK signaling contributes to activities in other pathways.
Figure 2
Figure 2
Simplified schematic illustration of the regulation of c-MET expression and activity in melanoma cells. (A) In normal skin, HGF is released mainly by fibroblasts to induce changes in melanocytes (paracrine signaling). In melanoma, autocrine signaling is also observed; (B) c-MET expression can be increased in melanoma cells through different mechanisms, including transcriptional regulation by MITF and reduced level of miRNAs targeting c-MET transcript. Activity of c-MET can be enhanced by elevated level of HGF produced and released by stromal cells (paracrine signaling) and melanoma cells (autocrine signaling) in response to diverse molecular stimuli, and with the regulatory contribution of ECM; Up- and down-arrows show enhanced and reduced levels of indicated molecules, respectively; (C) The enhanced activity of HGF/c-MET signaling in melanoma cells plays an important role in melanoma progression by supporting proliferation, survival, motility, and invasiveness, including niche formation. It is unclear whether HGF and/or c-MET are melanoma biomarkers, or whether the HGF/c-MET signaling contributes to the development of resistance to oncoprotein-targeted therapies.

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