| First Author | Coleman DJ | Year | 2015 |
| Journal | Mol Cancer Res | Volume | 13 |
| Issue | 1 | Pages | 186-96 |
| PubMed ID | 25189354 | Mgi Jnum | J:316236 |
| Mgi Id | MGI:6835121 | Doi | 10.1158/1541-7786.MCR-14-0164 |
| Citation | Coleman DJ, et al. (2015) Loss of keratinocytic RXRalpha combined with activated CDK4 or oncogenic NRAS generates UVB-induced melanomas via loss of p53 and PTEN in the tumor microenvironment. Mol Cancer Res 13(1):186-96 |
| abstractText | 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 (RXRalpha(ep-/-)) results in increased melanoma formation after chronic ultraviolet-B (UVB) irradiation compared with control mice with functional RXRalpha. Melanomas from both groups of bigenic RXRalpha(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 RXRalpha 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 RXRalpha. These results suggest a crucial role of keratinocytic RXRalpha 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 RXRalpha may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis. |
