Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes.
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.
Indra
Arup Kumar
AK
Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104; INSERM U596; ULP, Collège de France), Illkirch, Strasbourg, France. arup.indra@oregonstate.edu
Castaneda
Eduardo
E
Antal
Maria Cristina
MC
Jiang
Ming
M
Messaddeq
Nadia
N
Meng
Xiangjun
X
Loehr
Christiane V
CV
Gariglio
Patricio
P
Kato
Shigeaki
S
Wahli
Walter
W
Desvergne
Béatrice
B
Metzger
Daniel
D
Chambon
Pierre
P
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000473:pathology*; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009508:Nevus, Pigmented / Q000139:chemically induced / Q000473:pathology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology*; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate