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Malignant Transformation of DMBA/TPA-Induced Papillomas and Nevi in the Skin of Mice Selectively Lacking Retinoid-X-Receptor α in Epidermal Keratinocytes
- Source :
- Journal of Investigative Dermatology, Journal of Investigative Dermatology, Nature Publishing Group, 2007, 127 (5), pp.1250-60. ⟨10.1038/sj.jid.5700672⟩
- Publication Year :
- 2007
- Publisher :
- Elsevier BV, 2007.
-
Abstract
- Retinoid-X-receptor alpha (RXRalpha), a member of the nuclear receptor (NR) superfamily, is a ligand-dependent transcriptional regulatory factor. It plays a crucial role in NR signalling through heterodimerization with some 15 NRs. We investigated the role of RXRalpha and its partners on mouse skin tumor formation and malignant progression upon topical DMBA/TPA treatment. In mutants selectively ablated for RXRalpha in keratinocytes, epidermal tumors increased in size and number, and frequently progressed to carcinomas. As keratinocyte-selective peroxisome proliferator-activated receptor gamma (PPARgamma) ablation had similar effects, RXRalpha/PPARgamma heterodimers most probably mediate epidermal tumor suppression. Keratinocyte-selective RXRalpha-null and vitamin-D-receptor null mice also exhibited more numerous dermal melanocytic growths (nevi) than control mice, but only nevi from RXRalpha mutant mice progressed to invasive human-melanoma-like tumors. Distinct RXRalpha-mediated molecular events appear therefore to be involved, in keratinocytes, in cell-autonomous suppression of epidermal tumorigenesis and malignant progression, and in non-cell-autonomous suppression of nevi formation and progression. Our study emphasizes the crucial role of keratinocytes in chemically induced epidermal and melanocytic tumorigenesis, and raises the possibility that they could play a similar role in UV-induced tumorigenesis, notably in nevi formation and progression to melanoma.
- Subjects :
- Keratinocytes
Skin Neoplasms
DMBA
Peroxisome proliferator-activated receptor
MESH: Retinoid X Receptor alpha
Biochemistry
MESH: Carcinogens
Malignant transformation
Mice
0302 clinical medicine
MESH: Nevus, Pigmented
MESH: Animals
chemistry.chemical_classification
Nevus, Pigmented
0303 health sciences
integumentary system
Melanoma
MESH: Gene Expression Regulation, Neoplastic
MESH: Keratinocytes
Gene Expression Regulation, Neoplastic
Cell Transformation, Neoplastic
medicine.anatomical_structure
030220 oncology & carcinogenesis
Tetradecanoylphorbol Acetate
Keratinocyte
medicine.medical_specialty
MESH: Mice, Transgenic
9,10-Dimethyl-1,2-benzanthracene
Mice, Transgenic
Dermatology
Retinoid X receptor
Biology
03 medical and health sciences
Internal medicine
medicine
Animals
Nevus
MESH: Mice
Molecular Biology
MESH: Tetradecanoylphorbol Acetate
030304 developmental biology
Retinoid X Receptor alpha
Papilloma
MESH: Skin Neoplasms
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
MESH: 9,10-Dimethyl-1,2-benzanthracene
Cell Biology
medicine.disease
PPAR gamma
Endocrinology
Nuclear receptor
chemistry
MESH: PPAR gamma
MESH: Cell Transformation, Neoplastic
Carcinogens
Cancer research
Epidermis
MESH: Papilloma
MESH: Epidermis
Subjects
Details
- ISSN :
- 0022202X and 15231747
- Volume :
- 127
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Journal of Investigative Dermatology
- Accession number :
- edsair.doi.dedup.....8a7bec5d89ac16629fa37fc294a76acd
- Full Text :
- https://doi.org/10.1038/sj.jid.5700672