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Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice
- Source :
- Cell Death and Differentiation, Cell Death and Differentiation, Nature Publishing Group, In press, ⟨10.1038/s41418-020-0535-y⟩, Cell Death Differ
- Publication Year :
- 2020
-
Abstract
- 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/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-β1 with epidermal NRF2 and Nox4. In vitro investigations showed that PPARβ/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 PPARβ/δ in the epithelial-mesenchymal communication involved in cellular redox homeostasis. Ministry of Education (MOE) Accepted version This research/project is supported by Start-Up Grant (M4082040) and Ministry of Education, Singapore, under Academic Research Fund Tier 1 (2017-T1-002-103) to NST, (2015-T1-001-034) to WW and Start-Up Grant from the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore to WW and XW; the Région Midi-Pyrénées through the Chaire d’Excellence Pierre de Fermat and the Bonizzi-Theler-Stiftung to WW; SERB-DST, Govt. of India funded Ramanujan Fellowship Grant (SB/S2/RJN-087/2014) to MP
- Subjects :
- Keratinocytes
0301 basic medicine
Skin Neoplasms
Carcinogenesis
[SDV]Life Sciences [q-bio]
Tumor initiation
medicine.disease_cause
0302 clinical medicine
Gene Regulatory Networks
PPAR delta
Phosphorylation
Melanoma
biology
Chemistry
Biological sciences [Science]
Neoplasm Proteins
Tumor Burden
3. Good health
Kinasehydrogen Peroxide
medicine.anatomical_structure
NADPH Oxidase 4
030220 oncology & carcinogenesis
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
NF-E2-Related Factor 2
Mice, Transgenic
Article
Transforming Growth Factor beta1
B Raf
03 medical and health sciences
Downregulation and upregulation
medicine
Animals
PTEN
Fibroblast
PPAR-beta
Molecular Biology
Protein kinase B
Glycoproteins
Cell Biology
Fibroblasts
medicine.disease
Kinetics
030104 developmental biology
biology.protein
Cancer research
Epidermis
Skin cancer
Reactive Oxygen Species
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Subjects
Details
- Language :
- English
- ISSN :
- 13509047 and 14765403
- Database :
- OpenAIRE
- Journal :
- Cell Death and Differentiation, Cell Death and Differentiation, Nature Publishing Group, In press, ⟨10.1038/s41418-020-0535-y⟩, Cell Death Differ
- Accession number :
- edsair.doi.dedup.....18b79431bc8658ad77b9e96b23a36e31