title: Loss of keratinocytic RXRα combined with activated CDK4 or oncogenic NRAS generates UVB-induced melanomas via loss of p53 and PTEN in the tumor microenvironment.
abstract: Understanding the molecular mechanisms behind formation of melanoma, the deadliest form of skin cancer, is crucial for improved diagnosis and treatment. One key is to better understand the cross-talk between epidermal keratinocytes and pigment-producing melanocytes. Here, using a bigenic mouse model system combining mutant oncogenic NRAS(Q61K) (constitutively active RAS) or mutant activated CDK4(R24C/R24C) (prevents binding of CDK4 by kinase inhibitor p16(INK4A)) with an epidermis-specific knockout of the nuclear retinoid X receptor alpha (RXRα(ep-/-)) results in increased melanoma formation after chronic ultraviolet-B (UVB) irradiation compared with control mice with functional RXRα. Melanomas from both groups of bigenic RXRα(ep-/-) mice are larger in size with higher proliferative capacity, and exhibit enhanced angiogenic properties and increased expression of malignant melanoma markers. Analysis of tumor adjacent normal skin from these mice revealed altered expression of several biomarkers indicative of enhanced melanoma susceptibility, including reduced expression of tumor suppressor p53 and loss of PTEN, with concomitant increase in activated AKT. Loss of epidermal RXRα in combination with UVB significantly enhances invasion of melanocytic cells to draining lymph nodes in bigenic mice expressing oncogenic NRAS(Q61K) compared with controls with functional RXRα. These results suggest a crucial role of keratinocytic RXRα to suppress formation of UVB-induced melanomas and their progression to malignant cancers in the context of driver mutations such as activated CDK4(R24C/R24C) or oncogenic NRAS(Q61K).
  
  
  CONCLUSIONS
  These findings suggest that RXRα may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon. Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Coleman
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon. Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon.
authors.forename: Sharmeen
authors.initials: S
authors.lastname: Chagani
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon. Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hyter
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon. BioResource Research Program, College of Agricultural Sciences, Oregon State University, Corvallis, Oregon.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Sherman
authors.affiliation: College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.
authors.forename: Christiane V
authors.initials: CV
authors.lastname: Löhr
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon. Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon.
authors.forename: Gitali
authors.initials: G
authors.lastname: Ganguli-Indra
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, Oregon. Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon. Environmental Health Science Center, Oregon State University, Corvallis, Oregon. Department of Dermatology, Oregon Health and Science University, Portland, Oregon. Arup.Indra@oregonstate.edu.
authors.forename: Arup K
authors.initials: AK
authors.lastname: Indra
mesh_terms: D000818:Animals; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000473:pathology / Q000528:radiation effects; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D014466:Ultraviolet Rays
chemical_list: D008565:Membrane Proteins; D047490:Retinoid X Receptor alpha; D016159:Tumor Suppressor Protein p53; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human