{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T15:36:54Z","timestamp":1784561814076,"version":"3.55.0"},"reference-count":90,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T00:00:00Z","timestamp":1723680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000738","name":"United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service","doi-asserted-by":"publisher","award":["I01 BX003762"],"award-info":[{"award-number":["I01 BX003762"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service","doi-asserted-by":"publisher","award":["I01 BX005816"],"award-info":[{"award-number":["I01 BX005816"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Merit Review Award","doi-asserted-by":"publisher","award":["I01 BX003762"],"award-info":[{"award-number":["I01 BX003762"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Merit Review Award","doi-asserted-by":"publisher","award":["I01 BX005816"],"award-info":[{"award-number":["I01 BX005816"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed the transcriptomic changes observed in epidermal PPAR\u03b3-deficient mice (Pparg-\/-epi). A gene set enrichment analysis revealed a close association with epithelial malignancy, inflammatory cell chemotaxis, and cell survival. Single-cell sequencing of Pparg-\/-epi mice verified changes to the stromal compartment, including increased inflammatory cell infiltrates, particularly neutrophils, and an increase in fibroblasts expressing myofibroblast marker genes. A comparison of transcriptomic data from Pparg-\/-epi and publicly available human and\/or mouse actinic keratoses (AKs) and cutaneous squamous cell carcinomas (SCCs) revealed a strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AKs and SCCs. Both AKs and SCCs also had significantly reduced PPARG expression and PPAR\u03b3 activity z-scores. Smaller reductions in PPARA expression and PPAR\u03b1 activity and increased PPARD expression but reduced PPAR\u03b4 activation were also observed. Reduced PPAR activity was also associated with reduced PPAR\u03b1\/RXR\u03b1 activity, while LPS\/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably, these changes were not observed in normal sun-exposed skin relative to non-exposed skin. Finally, Ppara and Pparg were heavily expressed in sebocytes, while Ppard was highly expressed in myofibroblasts, suggesting that PPAR\u03b4 has a role in myofibroblast differentiation. In conclusion, these data provide strong evidence that PPAR\u03b3 and possibly PPAR\u03b1 represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs.<\/jats:p>","DOI":"10.3390\/cells13161356","type":"journal-article","created":{"date-parts":[[2024,8,15]],"date-time":"2024-08-15T03:49:36Z","timestamp":1723693776000},"page":"1356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Loss of PPAR\u03b3 Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association with Tumor Stromal Inflammation"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4923-2406","authenticated-orcid":false,"given":"Raymond L.","family":"Konger","sequence":"first","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, USA"},{"name":"Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Xuei","sequence":"additional","affiliation":[{"name":"Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethel","family":"Derr-Yellin","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2699-626X","authenticated-orcid":false,"given":"Yunlong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1124\/pr.58.4.2","article-title":"Overview of Nomenclature of Nuclear Receptors","volume":"58","author":"Germain","year":"2006","journal-title":"Pharmacol. 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