Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice.

Détails

ID Serval
serval:BIB_C09E5218BD1D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice.
Périodique
Cell death and differentiation
Auteur⸱e⸱s
Tan MWY, Sng M.K., Cheng H.S., Low Z.S., Leong BJJ, Chua D., Tan EHP, Chan JSK, Yip Y.S., Lee Y.H., Pal M., Wang X., Wahli W., Tan N.S.
ISSN
1476-5403 (Electronic)
ISSN-L
1350-9047
Statut éditorial
Publié
Date de publication
09/2020
Peer-reviewed
Oui
Volume
27
Numéro
9
Pages
2668-2680
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The incidence of nonmelanoma skin cancer (NMSC) has been increasing worldwide. Most studies have highlighted the importance of cancer-associated fibroblasts (CAFs) in NMSC progression. However much less is known about the communication between normal fibroblasts and epithelia; disruption of this communication affects tumor initiation and the latency period in the emergence of tumors. Delineating the mechanism that mediates this epithelial-mesenchymal communication in NMSC could identify more effective targeted therapies. The nuclear receptor PPARβ/δ in fibroblasts has been shown to modulate adjacent epithelial cell behavior, however, its role in skin tumorigenesis remains unknown. Using chemically induced skin carcinogenesis, we showed that FSPCre-Pparb/d <sup>ex4</sup> mice, whose Pparb/d gene was selectively deleted in fibroblasts, had delayed emergence and reduced tumor burden compared with control mice (Pparb/d <sup>fl/fl</sup> ). However, FSPCre-Pparb/d <sup>ex4</sup> -derived tumors showed increased proliferation, with no difference in differentiation, suggesting delayed tumor initiation. Network analysis revealed a link between dermal Pparb/d and TGF-β1 with epidermal NRF2 and Nox4. In vitro investigations showed that PPARβ/δ deficiency in fibroblasts increased epidermal Nox4-derived H <sub>2</sub> O <sub>2</sub> production, which triggered an NRF2-mediated antioxidant response. We further showed that H <sub>2</sub> O <sub>2</sub> upregulated NRF2 mRNA via the B-Raf-MEK1/2 pathway. The enhanced NRF2 response altered the activities of PTEN, Src, and AKT. In vivo, we detected the differential phosphorylation profiles of B-Raf, MEK1/2, PTEN, Src, and AKT in the vehicle-treated and chemically treated epidermis of FSPCre-Pparb/d <sup>ex4</sup> mice compared with that in Pparb/d <sup>fl/fl</sup> mice, prior to the first appearance of tumors in Pparb/d <sup>fl/fl</sup> . Our study revealed a role for fibroblast PPARβ/δ in the epithelial-mesenchymal communication involved in cellular redox homeostasis.
Mots-clé
Animals, Carcinogenesis/metabolism, Carcinogenesis/pathology, Epidermis/pathology, Fibroblasts/metabolism, Fibroblasts/pathology, Gene Regulatory Networks, Glycoproteins/metabolism, Keratinocytes/metabolism, Kinetics, Melanoma/metabolism, Melanoma/pathology, Mice, Transgenic, NADPH Oxidase 4/metabolism, NF-E2-Related Factor 2/metabolism, Neoplasm Proteins/metabolism, PPAR delta/deficiency, PPAR delta/metabolism, PPAR-beta/deficiency, PPAR-beta/metabolism, Phosphorylation, Reactive Oxygen Species/metabolism, Signal Transduction, Skin Neoplasms/genetics, Skin Neoplasms/metabolism, Skin Neoplasms/pathology, Transforming Growth Factor beta1/metabolism, Tumor Burden
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/04/2020 17:50
Dernière modification de la notice
05/10/2021 5:40
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