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

Daniel J. Coleman, Sharmeen Chagani, Stephen Hyter, Anna M. Sherman, Christiane V. Löhr, Xiaobo Liang, Gitali Ganguli-Indra, Arup K. Indra

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 NRASQ61K (constitutively active RAS) or mutant activated CDK4R24C/R24C (prevents binding of CDK4 by kinase inhibitor p16INK4A) with an epidermis-specific knockout of the nuclear retinoid X receptor alpha (RXRαep-/-) results in increased melanoma formation after chronic ultraviolet-B (UVB) irradiation compared with control mice with functional RXRα. Melanomas from both groups of bigenic RXRαep-/- 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 NRASQ61K 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 CDK4R24C/R24C or oncogenic NRASQ61K Implications: These findings suggest that RXRα may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis.

Original languageEnglish (US)
Pages (from-to)186-196
Number of pages11
JournalMolecular Cancer Research
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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