PreprintArticleVersion 1This version is not peer-reviewed
Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association With Tumor Stromal Inflammation
Version 1
: Received: 28 June 2024 / Approved: 1 July 2024 / Online: 2 July 2024 (04:09:49 CEST)
How to cite:
Konger, R. L.; Xuei, X.; Derr-Yellin, E.; Fang, F.; Gao, H.; Liu, Y. Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association With Tumor Stromal Inflammation. Preprints2024, 2024070153. https://doi.org/10.20944/preprints202407.0153.v1
Konger, R. L.; Xuei, X.; Derr-Yellin, E.; Fang, F.; Gao, H.; Liu, Y. Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association With Tumor Stromal Inflammation. Preprints 2024, 2024070153. https://doi.org/10.20944/preprints202407.0153.v1
Konger, R. L.; Xuei, X.; Derr-Yellin, E.; Fang, F.; Gao, H.; Liu, Y. Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association With Tumor Stromal Inflammation. Preprints2024, 2024070153. https://doi.org/10.20944/preprints202407.0153.v1
APA Style
Konger, R. L., Xuei, X., Derr-Yellin, E., Fang, F., Gao, H., & Liu, Y. (2024). Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association With Tumor Stromal Inflammation. Preprints. https://doi.org/10.20944/preprints202407.0153.v1
Chicago/Turabian Style
Konger, R. L., Hongyu Gao and Yunlong Liu. 2024 "Loss of PPARγ Expression and Signaling Is a Key Feature of Cutaneous Actinic Disease and Squamous Cell Carcinoma: Association With Tumor Stromal Inflammation" Preprints. https://doi.org/10.20944/preprints202407.0153.v1
Abstract
Given the importance of peroxisome proliferator-activated receptor (PPAR)-gamma in epidermal inflammation and carcinogenesis, we analyzed transcriptomic changes observed in epidermal PPARγ deficient mice (Pparg-/-epi). 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 (AK) and cutaneous squamous cell carcinomas (SCCs) revealed strong correlation between the datasets. Importantly, PPAR signaling was the top common inhibited canonical pathway in AK and SCC. Both AKs and SCCs also had significantly reduced PPARG expression and PPARγ activity z-scores. Smaller reductions in PPARA expression and PPARα activity and increased PPARD expression but reduced PPARδ activation were also observed. Reduced PPAR activity was also associated with reduced PPARα/RXRα activity while LPS/IL1-mediated inhibition of RXR activity was significantly activated in the tumor datasets. Notably. these changes are 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 a role for PPARδ in myofibroblast differentiation. In conclusion, these data indicate PPARγ and possibly PPARα represent key tumor suppressors by acting as master inhibitors of the inflammatory changes found in AKs and SCCs.
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
