Ablation of epidermal RXRα in cooperation with activated CDK4 and oncogenic NRAS generates spontaneous and acute neonatal UVB induced malignant metastatic melanomas

BMC Cancer

Research Article

Christiane V. Löhr¹  Evan L. Carpenter²  Rong Wang³  Sharmeen Chagani⁴  Gitali Ganguli-Indra⁵  Arup K. Indra⁶ 

[1] College of Veterinary Medicine, Oregon State University, Corvallis, 97331, Oregon, USA;Department of Pharmaceutical Sciences, College of Pharmacy, OSU, 97331, Corvallis, OR, USA;Department of Pharmaceutical Sciences, College of Pharmacy, OSU, 97331, Corvallis, OR, USA;Linus Pauling Institute, OSU, Corvallis, OR, USA;Molecular and Cellular Biology Program, OSU, 97331, Corvallis, OR, USA;Department of Pharmaceutical Sciences, College of Pharmacy, OSU, 97331, Corvallis, OR, USA;Molecular and Cellular Biology Program, OSU, 97331, Corvallis, OR, USA;Department of Pharmaceutical Sciences, College of Pharmacy, OSU, 97331, Corvallis, OR, USA;Knight Cancer Institute, Oregon Health & Science University (OHSU), 97239, Portland, OR, USA;Molecular and Cellular Biology Program, OSU, 97331, Corvallis, OR, USA;Department of Pharmaceutical Sciences, College of Pharmacy, OSU, 97331, Corvallis, OR, USA;Linus Pauling Institute, OSU, Corvallis, OR, USA;Knight Cancer Institute, Oregon Health & Science University (OHSU), 97239, Portland, OR, USA;Department of Dermatology, OHSU, 97239, Portland, OR, USA;

关键词: Keratinocytes;    Melanocytes;    Acute UVB;    Retinoid-X-receptor α (RXRα);    Malignant melanoma;    Trigenic;    Spontaneous melanoma;    NRAS;    CDK4;    Microenvironment;   

DOI  :  10.1186/s12885-017-3714-6

 received in 2016-09-14, accepted in 2017-10-30,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundUnderstanding the underlying molecular mechanisms involved in the formation of cutaneous malignant melanoma is critical for improved diagnosis and treatment. Keratinocytic nuclear receptor Retinoid X Receptor α (RXRα) has a protective role against melanomagenesis and is involved in the regulation of keratinocyte and melanocyte homeostasis subsequent acute ultraviolet (UV) irradiation.MethodsWe generated a trigenic mouse model system (RXRαep−/−| Tyr-NRASQ61K | CDK4R24C/R24C) harboring an epidermal knockout of Retinoid X Receptor α (RXRαep−/−), combined with oncogenic NRASQ61K (constitutively active RAS) and activated CDK4R24C/R24C (constitutively active CDK4). Those mice were subjected to a single neonatal dose of UVB treatment and the role of RXR α was evaluated by characterizing the molecular and cellular changes that took place in the untreated and UVB treated trigenic RXRαep−/− mice compared to the control mice with functional RXRα.ResultsHere we report that the trigenic mice develops spontaneous melanoma and exposure to a single neonatal UVB treatment reduces the tumor latency in those mice compared to control mice with functional RXRα. Melanomas from the trigenic RXRαep−/− mice are substantial in size, show increased proliferation, exhibit increased expression of malignant melanoma markers and exhibit enhanced vascularization. Altered expression of several biomarkers including increased expression of activated AKT, p21 and cyclin D1 and reduced expression of pro-apoptotic marker BAX was observed in the tumor adjacent normal (TAN) skin of acute ultraviolet B treated trigenic RXRαep−/− mice. Interestingly, we observed a significant increase in p21 and Cyclin D1 in the TAN skin of un-irradiated trigenic RXRαep−/− mice, suggesting that those changes might be consequences of loss of functional RXRα in the melanoma microenvironment. Loss of RXRα in the epidermal keratinocytes in combination with oncogenic NRASQ61K and CDK4R24C/R24C mutations in trigenic mice led to significant melanoma invasion into the draining lymph nodes as compared to controls with functional RXRα.ConclusionsOur study demonstrates the protective role of keratinocytic RxRα in (1) suppressing spontaneous and acute UVB-induced melanoma, and (2) preventing progression of the melanoma to malignancy in the presence of driver mutations like activated CDK4R24C/R24C and oncogenic NRASQ61K.

【 授权许可】

CC BY   
© The Author(s). 2017