Abstract
Seborrheic keratosis, which is a benign tumor composed of epidermal keratinocytes, develops common in the elderly. Uric acid generated by upregulated guanine deaminase (GDA) has been identified to cause UV-induced keratinocyte senescence in seborrheic keratosis. Seborrheic keratosis is also frequently pigmented. Growing evidences indicate that hyperuricemia is a risk factor of acanthosis nigricans, an acquired skin hyperpigmentation. The objective of this study was to investigate role of GDA and its metabolic end product, uric acid, in hyperpigmentation of patients with seborrheic keratosis using their lesional and non-lesional skin specimen sets and cultured primary human epidermal keratinocytes with or without GDA overexpression or uric acid treatment. GDA-overexpressing keratinocytes or their conditioned media containing uric acid increased expression levels of MITF and tyrosinase in melanocytes. Uric acid released from keratinocytes was facilitated by ABCG2 transporter with the help of PDZK1 interaction. Released uric acid was taken by URAT1 transporter in melanocytes, stimulating melanogenesis through p38 MAPK activation. Overall, GDA upregulation in seborrheic keratosis plays a role in melanogenesis via its metabolic end product uric acid, suggesting that seborrheic keratosis as an example of hyperpigmentation associated with photoaging.
Highlights
Seborrheic keratosis is a common benign skin tumor characterized by keratinocyte proliferation
We have recently found that guanine deaminase (GDA) expression in keratinocytes induced by repeated ultraviolet (UV) exposure is involved in UV-induced keratinocyte senescence in seborrheic keratosis via uric acid, a guanine metabolite [5], supporting a causative role of photoaging in seborrheic keratosis
The role of upregulated GDA in melanogenesis was examined in primary cultured adult normal human keratinocytes with or without GDA overexpression cocultured with primary cultured adult normal human melanocytes
Summary
Seborrheic keratosis is a common benign skin tumor characterized by keratinocyte proliferation. Tyrosinase and tyrosinaserelated proteins (TRPs) are key enzymes for melanogenesis. Genes encoding tyrosinase and TRPs contain common transcription starting sites, micropthalmia-associated transcription factor (MITF) binding sites. Seborrheic keratosis frequently presents as sharply demarcated light brown to black papules due to great amount of melanin in its keratinocytes. It is considered as one of common facial pigmentary disorders of greatest concern along with melasma [7]. The role of uric acid in skin hyperpigmentation is unknown, hyperuricemia is well-known to be associated with metabolic syndrome [8,9,10,11,12]
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