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Cell Death Differ ; 27(9): 2668-2680, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32313198

RESUMEN

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 PPARß/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/dex4 mice, whose Pparb/d gene was selectively deleted in fibroblasts, had delayed emergence and reduced tumor burden compared with control mice (Pparb/dfl/fl). However, FSPCre-Pparb/dex4-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-ß1 with epidermal NRF2 and Nox4. In vitro investigations showed that PPARß/δ deficiency in fibroblasts increased epidermal Nox4-derived H2O2 production, which triggered an NRF2-mediated antioxidant response. We further showed that H2O2 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/dex4 mice compared with that in Pparb/dfl/fl mice, prior to the first appearance of tumors in Pparb/dfl/fl. Our study revealed a role for fibroblast PPARß/δ in the epithelial-mesenchymal communication involved in cellular redox homeostasis.


Asunto(s)
Fibroblastos/metabolismo , Fibroblastos/patología , PPAR delta/deficiencia , PPAR-beta/deficiencia , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Epidermis/patología , Redes Reguladoras de Genes , Glicoproteínas/metabolismo , Queratinocitos/metabolismo , Cinética , Melanoma/metabolismo , Melanoma/patología , Ratones Transgénicos , NADPH Oxidasa 4/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas de Neoplasias/metabolismo , PPAR delta/metabolismo , PPAR-beta/metabolismo , Fosforilación , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genética , Factor de Crecimiento Transformador beta1/metabolismo , Carga Tumoral
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