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.
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Data availability
The datasets for microarray analysis during the current study are available through the Gene Expression Omnibus Series accession number GSE71419. The data in Fig. S4 are in whole based upon data generated by the TCGA Research Network (http://cancergenome.nih.gov/).
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Acknowledgements
We thank all individuals who take part in this research. MWYT is a recipient of Interdisciplinary Graduate Scholarship from Nanyang Technological University Singapore. ZSL is a recipient of Research Scholarship from Lee Kong Chian School of Medicine, Nanyang Technological University Singapore.
Funding
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.
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Animal experiments were carried out in accordance with the guidelines of the institutional animal care and use committee (ARF-SBS/NIE-A0324, A0321, A0112AZ, and A0216AZ) of Nanyang Technological University Singapore, Singapore.
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Tan, M.W.Y., Sng, M.K., Cheng, H.S. et al. Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice. Cell Death Differ 27, 2668–2680 (2020). https://doi.org/10.1038/s41418-020-0535-y
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DOI: https://doi.org/10.1038/s41418-020-0535-y
