α-MSH stimulation contributes to TGF-β1 production via MC1R-MITF signaling pathway in melanoma cell

Abstract

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that play critical roles in melanoma progression. Although the impact of TGF-β signaling on melanoma progression has been well characterized, little is known about the molecular mechanisms that control TGF-β production in melanoma cells. In this study, we describe a novel role for Melanocortin Receptor 1 (MC1R) in the regulation of TGF-β production. MC1R is a cell surface endocytic receptor expressed in melanoma cells and serves as a receptor for α-Melanocyte Stimulating Hormone (α-MSH). The activation of MC1R with α-MSH resulted in increased levels of TGF-β, which was mediated by ERK1/2 and p38 signaling pathways. Furthermore, Microphthalmia Transcription Factor (MITF), the master regulator of melanocytes, was found to act downstream of MC1R to regulate TGF-β production. Targeting of MC1R-MITF axis was effective to decrease TGF-β production, and resulted in delayed tumor growth of B16 melanoma in vivo. Collectively, these results give new insight into the molecular mechanisms that control TGF-β production in melanoma cells.

Comparative microRNA-seq Analysis Depicts Candidate miRNAs Involved in Skin Color Differentiation in Red Tilapia

“…Among the targets, mc1r , the most important regulator of melanogenesis, positively regulated cyclic AMP (cAMP) response-element binding protein ( creb ) and downstream mitf to increase melanin synthesis [ 29 ]; wnt4 was also reported to be maintained at higher levels in normal peripheral retinal pigment epithelium cells in dark agouti rats [ 30 ]. In normal melanocytes, the activation of Mc1r-cAMP-Mift pigmentation signaling cascade has been proved to induce the production of transforming growth factor (TGF)-β1 in transformed melanocytes in human melanoma cells and play crucial roles in ultraviolet (UV) light exposure-induced skin pigmentation [ 31 , 32 ]. Moreover, the inactivation of the Mc1r-cAMP-Mift signaling cascade was essential for sesamol-decreased pigment formation and melanogenesis in melanocyte cells and zebrafish [ 33 ].…”