title: Loss of nuclear receptor RXRα in epidermal keratinocytes promotes the formation of Cdk4-activated invasive melanomas.
abstract: Keratinocytes contribute to melanocyte transformation by affecting their microenvironment, in part through the secretion of paracrine factors. Here we report a loss of expression of nuclear receptor RXRα in epidermal keratinocytes during human melanoma progression. In the absence of keratinocytic RXRα, in combination with mutant Cdk4, cutaneous melanoma was generated that metastasized to lymph nodes in a bigenic mouse model. Expression of several keratinocyte-derived mitogenic growth factors (Et-1, Hgf, Scf, α-MSH and Fgf 2 ) was elevated in skin of bigenic mice, whereas Fas, E-cadherin and Pten, implicated in apoptosis, cellular invasion and melanomagenesis, respectively, were downregulated within the microdissected melanocytic tumors. We demonstrated that RXRα is recruited on the proximal promoter of both Et-1 and Hgf, possibly directly regulating their transcription in keratinocytes. These studies demonstrate the contribution of keratinocytic paracrine signaling during the cellular transformation and malignant conversion of melanocytes.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyter
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bajaj
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Liang
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: Gitali
authors.initials: G
authors.lastname: Ganguli-Indra
authors.forename: Arup Kumar
authors.initials: AK
authors.lastname: Indra
mesh_terms: D000818:Animals; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D000078404:Epidermal Cells; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019899:Paracrine Communication; D011401:Promoter Regions, Genetic; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D019332:Endothelin-1; D047490:Retinoid X Receptor alpha; D017228:Hepatocyte Growth Factor; D051358:Cyclin-Dependent Kinase 4