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

Autor: Yin Hao Lee, Nguan Soon Tan, Hong Sheng Cheng, Zun Siong Low, Jeremy Soon Kiat Chan, Ming Keat Sng, Benjamin Jia Juin Leong, Walter Wahli, Eddie Han Pin Tan, Damien Chua, Mark Wei Yi Tan, Mintu Pal, Xiaomeng Wang, Yun Sheng Yip
Přispěvatelé: School of Biological Sciences, Interdisciplinary Graduate School (IGS), Lee Kong Chian School of Medicine (LKCMedicine), Institute of Molecular and Cell Biology, A*STAR, NTU Institute for Health Technologies, Nanayang Technological University (NTU), Nanayang Technological University, Council of Scientific and Industrial Research [India] (CSIR), Agency for science, technology and research [Singapore] (A*STAR), Institute of Ophthalmology [London], University College of London [London] (UCL), Singapore Eye Research Institute [Singapore] (SERI), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
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
Zdroj: Cell Death and Differentiation
Cell Death and Differentiation, Nature Publishing Group, In press, ⟨10.1038/s41418-020-0535-y⟩
Cell Death Differ
ISSN: 1350-9047
1476-5403
Popis: 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
Databáze: OpenAIRE
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