TitleLoss of keratinocytic RXRα combined with activated CDK4 or oncogenic NRAS generates UVB-induced melanomas via loss of p53 and PTEN in the tumor microenvironment.
Publication TypeJournal Article
Year of Publication2015
AuthorsColeman, DJ, Chagani, S, Hyter, S, Sherman, AM, Löhr, CV, Liang, X, Ganguli-Indra, G, Indra, AK
JournalMol Cancer Res
Volume13
Issue1
Pagination186-96
Date Published2015 Jan
ISSN1557-3125
KeywordsAnimals, Cyclin-Dependent Kinase 4, Gene Expression Regulation, Neoplastic, GTP Phosphohydrolases, Humans, Keratinocytes, Melanoma, Membrane Proteins, Mice, Mutation, PTEN Phosphohydrolase, Retinoid X Receptor alpha, Tumor Microenvironment, Tumor Suppressor Protein p53, Ultraviolet Rays
Abstract

UNLABELLED: 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).

IMPLICATIONS: These findings suggest that RXRα may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis.

DOI10.1158/1541-7786.MCR-14-0164
Alternate JournalMol. Cancer Res.
PubMed ID25189354
PubMed Central IDPMC4297739
Grant ListES016629-01A1 / ES / NIEHS NIH HHS / United States
P30 ES00210 / ES / NIEHS NIH HHS / United States
R01 ES016629 / ES / NIEHS NIH HHS / United States
T32 CA106195 / CA / NCI NIH HHS / United States
T32CA106195 / CA / NCI NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States