Malignant Transformation of DMBA/TPA-Induced Papillomas and Nevi in the Skin of Mice Selectively Lacking Retinoid-X-Receptor α in Epidermal Keratinocytes

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.

Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

“…It has since become apparent that increased cancer risk from high fat diets is due in part to higher levels of oxidized lipid species 74,75 . A potential role for PPARγ in cutaneous carcinogenesis is indicated by a recent study demonstrating that mice deficient in either epidermal PPARγ or its heterodimer partner, RXR, exhibit increased rates of cutaneous neoplasia following a chemical carcinogenesis protocol 76 . This study is in agreement with an earlier study demonstrating that heterozygous germ-line loss of PPARγ also augments chemicallyinduced cutaneous neoplasia 77 .…”

Chemopreventive effects of wild carrot oil against 7,12-dimethyl benz(a)anthracene-induced squamous cell carcinoma in mice

“…Three weeks after the initiation, papillomas were promoted twice weekly at Day 1 and Day 4 with a topical application of 8 nmol TPA in 0.2 mL acetone. TPA solution was delivered to the dorsal skin of individual mice twice per week for the duration of the experiment (20 weeks) (Indra et al, 2007).…”

“…The present study was conducted to evaluate the antitumor-promoting effects of D. carota oil extract (DCOE) on skin carcinogenesis established through the 7,12-dimethyl benz(a)anthracene (DMBA)-initiation-12-O-tetradecanoyl phorobol-13-acetate (TPA) promotion mouse skin carcinogenesis model (Indra et al, 2007). The antitumor activity was evaluated using three different routes of administration: topical application, gavage, and intraperitoneal injections.…”

All-Trans Retinoic Acid Suppresses Stat3 Signaling during Skin Carcinogenesis

“…All-trans retinoic acid (ATRA) has long been known as one of the most effective suppressors of tumor formation in the two-stage skin carcinogenesis model (9,10). Recent studies using mice genetically engineered for keratinocyte-specific knockout of multiple nuclear receptors, indicates that it is the retinoid X receptor-α isoform, when heterodimerized with another nuclear receptor family member, peroxisome proliferator-activated receptor-γ, that mediates tumor suppression in the two-stage model (11).…”