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Title: Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice
Authors: Tan, Mark Wei Yi
Sng, Ming Keat
Cheng, Hong Sheng
Low, Zun Siong
Leong, Benjamin Jia Juin
Chua, Damien
Tan, Eddie Han Pin
Chan, Jeremy Soon Kiat
Yip, Yun Sheng
Lee, Yin Hao
Pal, Mintu
Wang, Xiaomeng
Wahli, Walter
Tan, Nguan Soon
Keywords: Science::Biological sciences
Issue Date: 2020
Source: Tan, M. W. Y., Sng, M. K., Cheng, H. S., Low, Z. S., Leong, B. J. J., Chua, D., . . . Tan, N. S. (2020). Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice. Cell Death & Differentiation, 27(9), 2668–2680. doi:10.1038/s41418-020-0535-y
Journal: Cell death and differentiation 
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.
ISSN: 1350-9047
DOI: 10.1038/s41418-020-0535-y
Schools: School of Biological Sciences 
Interdisciplinary Graduate School (IGS) 
Lee Kong Chian School of Medicine (LKCMedicine) 
Organisations: Institute of Molecular and Cell Biology, A*STAR
Research Centres: NTU Institute for Health Technologies 
Rights: © 2020 Macmillan Publishers Ltd. All rights reserved. This paper was published in Cell death and differentiation and is made available with permission of Macmillan Publishers Ltd.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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