Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes.

TitleMalignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes.
Publication TypeJournal Article
Year of Publication2007
AuthorsIndra AK, Castaneda E, Antal MC, Jiang M, Messaddeq N, Meng X, Loehr CV, Gariglio P, Kato S, Wahli W, Desvergne B, Metzger D, Chambon P
JournalThe Journal of investigative dermatology
Volume127
Issue5
Pagination1250-60
Date Published2007 May
ISSN1523-1747
Keywords9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinogens, Cell Transformation, Neoplastic, Epidermis, Gene Expression Regulation, Neoplastic, Keratinocytes, Mice, Mice, Transgenic, Nevus, Pigmented, Papilloma, PPAR gamma, Retinoid X Receptor alpha, Skin Neoplasms, Tetradecanoylphorbol Acetate
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.

Alternate JournalJ. Invest. Dermatol.