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 |
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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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