title: Reduced WIF-1 expression stimulates skin hyperpigmentation in patients with melasma.
abstract: The expression of Wnt inhibitory factor-1 (WIF-1) gene, which was detected by a microarray analysis of hyperpigmented and normally pigmented skin sets of melasma patients, was significantly reduced in the hyperpigmented skin from melasma patients, but not in healthy controls, regardless of UV irradiation. Wnt signals regulate skin pigmentation; however, WIF-1 is expressed in cultured skin keratinocytes and fibroblasts, but not in melanocytes. Therefore, we examined whether WIF-1 knockdown in neighboring keratinocytes and fibroblasts plays a role in melasma. Additionally, the effect of WIF-1 overexpression on the amelioration of hyperpigmentation was examined. WIF-1 knockdown, either in fibroblasts or in keratinocytes, significantly stimulated tyrosinase expression and melanosome transfer, whereas melanocytes with WIF-1 overexpression significantly reduced those parameters. The WIF-1 knockdown decreased glycogen synthase kinase-3β (GSK-3β), β-catenin, and NFATc2 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 2) phosphorylation and increased microphthalmia-associated transcription factor (MITF) expression as in melanocytes with Wnt-1 overexpression, whereas the WIF-1 overexpression reversed the results. Expression of Wnts, both canonical and noncanonical, was increased in the hyperpigmented skin of melasma patients. Collectively, WIF-1 downregulation, which may occur in epidermal keratinocytes and in dermal fibroblasts, is involved in melasma development because of the stimulation of melanogenesis and melanosome transfer through upregulation of the canonical and the noncanonical Wnt signaling pathway.
authors.affiliation: Department of Dermatology, Dongguk University Ilsan Hospital, Goyang-si, Gyeonggi-do, South Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Tae-Ryong
authors.initials: TR
authors.lastname: Lee
authors.forename: Ai-Young
authors.initials: AY
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017495:Hyperpigmentation / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D008544:Melanocytes / Q000378:metabolism; D008548:Melanosis / Q000235:genetics / Q000378:metabolism*; D020460:Melanosomes / Q000235:genetics / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000096:biosynthesis; D050778:NFATC Transcription Factors / Q000032:analysis; D010766:Phosphorylation; D040081:Protein Array Analysis; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495270:CTNNB1 protein, human; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051176:beta Catenin; D014442:Monophenol Monooxygenase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3