Aldo-Keto Reductase 1C3 Is Expressed in Differentiated Human Epidermis, Affects Keratinocyte Differentiation, and Is Upregulated in Atopic Dermatitis

Abstract

Aldo-keto reductase 1C3 (AKR1C3) has been shown to mediate the metabolism of sex hormones and prostaglandin D2 (PGD2), a lipid mediator that promotes skin inflammation in atopic dermatitis (AD). Since both play a role in skin function and pathology, we first sought to investigate the expression pattern of AKR1C3 in normal human epidermis. Immunofluorescence revealed a strong expression of AKR1C3 in the differentiated suprabasal layers compared with the basal layer. Western blot and quantitative PCR confirmed that AKR1C3 expression was also upregulated in differentiation-induced primary human keratinocytes (PHK). To investigate the functional role of AKR1C3 during PHK differentiation, its expression and activity (measured as PGD2 reduction to 9α,11β-PGF2 by ELISA) were impaired by siRNA or 2′-hydroxyflavanone, respectively. Cytokeratin 10 (K10) and loricrin expression were then examined by western blot revealing altered expression of these differentiation markers. Finally, following an observation that the AD-associated mediator, PGD2 upregulated AKR1C3 expression in PHK, we used immunofluorescence to examine AKR1C3 expression in AD and psoriasis lesions. AKR1C3 was found to be upregulated in AD but not in psoriasis lesions compared with non-lesional skin. Our work demonstrates a function for AKR1C3 in differentiation-associated gene regulation and also suggests a role in supporting inflammation in AD.

Aldo‐keto reductase 1C3 is overexpressed in skin squamous cell carcinoma (SCC) and affects SCC growth via prostaglandin metabolism

“…Different levels of AKR1C3 expression were detected within the epithelial SCC mass, with stronger immunoreactivity found in areas of moderately differentiated keratinocytes. Interestingly, this distribution pattern aligns with its relatively higher expression in the spinous and granular layers of normal epidermis and in differentiated cultured keratinocytes .…”

“…Cellular enzymatic activity of AKR1C3 was assessed by measuring the conversion of PGD 2 to 9 α 11 β ‐PGF 2 using ELISA (catalogue: 516521; Cayman Chemical, Ann Arbor, MI, USA) as previously described . Cells were seeded in six‐well plates and allowed to reach 90% confluence.…”

“…Protein extraction and western blot procedures were carried out as previously described . For all experiments 50 μ g protein was used and the primary antibodies were diluted as follows: Anti‐AKR1C3 1:1000; anti‐human β ‐actin 1:2000.…”

Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells

“…The down regulation of a number of HDACs following AKR1C3 knockdown supports the hypothesis that AKR1C3 in some manner is able to regulate enzymes governing epigenetic gene regulation, explaining why the cells gain sensitivity to SAHA. Interestingly, the upregulation of IKBkB correlates with previous findings suggesting a link between AKR1C3 and NFkB signaling pathways [65,66]. More broadly to establish the association of AKR1C3 with tumor status The Cancer Genome Atlas (TCGA) data was examined to identify genes associated with AKR1C3 signalling, and in parallel the AR and PPARg signalling.…”

Identification of a gene signature of a pre-transformation process by senescence evasion in normal human epidermal keratinocytes

“…Among the genes of the pathway, we choose to invalidate AKR1C2 and AKR1C3 because they were with CYP4B1 the most highly up-regulated and because they are known to be physiologically expressed in the epidermis [23-25]. AKR1Cs are a family of cytosolic NADP (H)-dependent oxidoreductases involved in the metabolism of steroids (C1-C3), prostaglandins (C3), polyaromatic hydrocarbons (C1-C3) and xenobiotics (C1, C2, C4,) [26-28].…”