Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice.,Cell Death and Differentiation

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Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2020-04-20 , DOI: 10.1038/s41418-020-0535-y
Mark Wei Yi Tan _{1,

2} , Ming Keat Sng ₃ , Hong Sheng Cheng _{1,

3} , Zun Siong Low ₃ , Benjamin Jia Juin Leong ₁ , Damien Chua ₁ , Eddie Han Pin Tan ₁ , Jeremy Soon Kiat Chan ₁ , Yun Sheng Yip _{1,

3} , Yin Hao Lee ₃ , Mintu Pal ₄ , Xiaomeng Wang _{3,

5,

6,

7} , Walter Wahli _{3,

8,

9} , Nguan Soon Tan _{1,

3}

Affiliation

School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore, 637551, Singapore.
NTU Institute for Health Technologies, Interdisciplinary Graduate School, Nanyang Technological University Singapore, Singapore, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore, 308232, Singapore.
Biotechnology Group, Biological Sciences and Technology Division, CSIR-North East Institute of Science and Technology, Academy of Scientific and Innovative Research, Jorhat, Assam, 785006, India.
Institute of Molecular and Cell Biology, Agency for Science Technology & Research, 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.
Department of Cell Biology, Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
Singapore Eye Research Institute, The Academia, 20 College Road Discovery Tower Level 6, Singapore, 169856, Singapore.
INRA ToxAlim, UMR1331, Chemin de Tournefeuille, Toulouse Cedex 3, France.
Center for Integrative Genomics, University of Lausanne, Le Génopode, Lausanne, Switzerland.

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.

中文翻译：

成纤维细胞 PPARβ/δ 的缺乏会减少小鼠的非黑色素瘤皮肤癌。

非黑色素瘤皮肤癌 (NMSC) 的发病率在全球范围内呈上升趋势。大多数研究都强调了癌症相关成纤维细胞 (CAF) 在 NMSC 进展中的重要性。然而，对正常成纤维细胞和上皮细胞之间的交流知之甚少。这种通讯的中断会影响肿瘤的发生和肿瘤出现的潜伏期。描述在 NMSC 中介导这种上皮间充质通讯的机制可以确定更有效的靶向治疗。成纤维细胞中的核受体 PPARβ/δ 已被证明可调节邻近的上皮细胞行为，然而，其在皮肤肿瘤发生中的作用仍然未知。使用化学诱导的皮肤癌发生，我们发现 FSPCre-Pparb/dex4 小鼠，其 Pparb/d 基因在成纤维细胞中被选择性删除，与对照小鼠（Pparb / dfl / fl）相比，出现延迟并减少了肿瘤负荷。然而，FSPCre-Pparb/dex4 衍生的肿瘤显示增殖增加，分化没有差异，表明肿瘤起始延迟。网络分析揭示了真皮 Pparb/d 和 TGF-β1 与表皮 NRF2 和 Nox4 之间的联系。体外研究表明，成纤维细胞中 PPARβ/δ 缺乏会增加表皮 Nox4 衍生的 H2O2 产生，从而引发 NRF2 介导的抗氧化反应。我们进一步表明 H2O2 通过 B-Raf-MEK1/2 通路上调 NRF2 mRNA。增强的 NRF2 反应改变了 PTEN、Src 和 AKT 的活性。在体内，我们检测到 B-Raf、MEK1/2、PTEN、Src、与 Pparb/dfl/fl 小鼠相比，在 Pparb/dfl/fl 中首次出现肿瘤之前，FSPCre-Pparb/dex4 小鼠的载体处理和化学处理的表皮中的 AKT 和 AKT。我们的研究揭示了成纤维细胞 PPARβ/δ 在参与细胞氧化还原稳态的上皮间充质通讯中的作用。

更新日期：2020-04-24

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