beta-Defensin 103 characterizes a distinct molecular phenotype of human acral melanoma, by its correlated expression with IL-17A & IFN gamma-mediated immune genes, as well as MC1R-mediated pigmentation signatures

초록

b-Defensin 103 (DEFB103B), highly expressed in stratum corneum and regulated by IL-17A and IFNg, was recently identified as an MC1R receptor agonist, which increases levels of pigmentation in mammals, and regulates melanoma cell migration. Our human melanoma research showed that high expression of DEFB103B characterizes acral melanoma, which is associated with a poor prognosis, and is genetically different from other subtypes of melanoma. We first compared gene expression profiles of acral melanoma (n¼10 for array, n¼20 for PCR) to non-acral melanoma (n¼21 for array), acral skin (n¼4 for array, n¼7 for PCR) and non-acral skin (n¼12 for array and PCR). Compared to non-acral melanoma, acral melanoma was characterized by higher expression of antimicrobial peptides (DEFB103B, DEFB4A, and S100A7A) and activation of IL-17 and IFNg immune pathways (FCH>2, FDR0.05). The enrichment of melanoma signatures was not different between acral vs. non-acral melanoma (p>0.05). Compared to normal skin, the expression of DEFB103B, IL-17A, IFNg, MC1R, and TYR was increased in acral melanoma (p<0.05). In addition, the expression of DEFB103B in acral melanoma was correlated with the number of CD11c+ dendritic cells in the tissue (¼0.77), the expression of IL-17A pathway genes (IL-17A (¼0.83), IL-17F (¼0.50), IL-23 (¼0.49), IL-19 (¼0.86), IL-20 (¼0.97)), IFNg pathway genes (IFN (¼0.49)), and MC1Rmediated signatures (MITF (¼0.62), TYR (¼0.49)) (p<0.05). Those correlations were not significant in normal skin (p>0.05). Thus, we propose that DEFB103B is a novel access of keratinocytes to melanocytes via MC1R, which could be a potential mechanism for abnormally dark pigmentation and invasive tumor progression of acral melanoma.