ROS release by PPARβ/δ-null fibroblasts reduces tumor load through epithelial antioxidant response

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ROS release by PPARβ/δ-null fibroblasts reduces tumor load through epithelial antioxidant response
Title:
ROS release by PPARβ/δ-null fibroblasts reduces tumor load through epithelial antioxidant response
Other Titles:
Oncogene
Publication Date:
25 January 2018
Citation:
Tan, E. H. P., Sng, M. K., How, I. S. B., Chan, J. S. K., Chen, J., Tan, C. K., … Tan, N. S. (2018). ROS release by PPARβ/δ-null fibroblasts reduces tumor load through epithelial antioxidant response. Oncogene, 37(15), 2067–2078. doi:10.1038/s41388-017-0109-8
Abstract:
Tumor stroma has an active role in the initiation, growth, and propagation of many tumor types by secreting growth factors and modulating redox status of the microenvironment. Although PPARβ/δ in fibroblasts was shown to modulate oxidative stress in the wound microenvironment, there has been no evidence of a similar effect in the tumor stroma. Here, we present evidence of oxidative stress modulation by intestinal stromal PPARβ/δ, using a FSPCre-Pparb/d−/− mouse model and validated it with immortalized cell lines. The FSPCre-Pparb/d−/− mice developed fewer intestinal polyps and survived longer when compared with Pparb/dfl/fl mice. The pre-treatment of FSPCre-Pparb/d−/− and Pparb/dfl/fl with antioxidant N-acetyl-cysteine prior DSS-induced tumorigenesis resulted in lower tumor load. Gene expression analyses implicated an altered oxidative stress processes. Indeed, the FSPCre-Pparb/d−/− intestinal tumors have reduced oxidative stress than Pparb/dfl/fl tumors. Similarly, the colorectal cancer cells and human colon epithelial cells also experienced lower oxidative stress when co-cultured with fibroblasts depleted of PPARβ/δ expression. Therefore, our results establish a role for fibroblast PPARβ/δ in epithelial–mesenchymal communication for ROS homeostasis.
License type:
Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
Funding Info:
This work was supported by Singapore Ministry of Education under Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2014-T2-1-012) and Academic Research Fund Tier 1 (RG134/15) to NST, and by the Lee Kong Chian School of Medicine, Nanyang Technological University Start-up Grant to WW.
Description:
ISSN:
1476-5594
0950-9232
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