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

Autor: Chek Kun Tan, Jeremy Soon Kiat Chan, Ming Keat Sng, Ivan Shun Bo How, Jiapeng Chen, Nguan Soon Tan, Walter Wahli, Eddie Han Pin Tan
Přispěvatelé: School of Biological Sciences, Nanyang Technological University (NTU), Lee Kong Chian School of Medicine, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), 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-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Agency for Science Technology and Research, KK Research Centre, KK Women’s and Children’s Hospital (KKH), Tan, Eddie Han Pin, Tan, Nguan Soon, Lee Kong Chian School of Medicine (LKCMedicine)
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Stromal cell
[SDV]Life Sciences [q-bio]
Animals
Antioxidants/metabolism
Cells
Cultured
Epithelial Cells/drug effects
Epithelial Cells/metabolism
Fibroblasts/metabolism
Gene Knockdown Techniques
HCT116 Cells
HT29 Cells
Humans
Mice
Mice
Knockout
PPAR delta/genetics
PPAR-beta/genetics
Reactive Oxygen Species/metabolism
Reactive Oxygen Species/pharmacology
Tumor Burden/drug effects
Tumor Burden/genetics
Biology
Brief Communication
medicine.disease_cause
Antioxidants
03 medical and health sciences
Genetics
medicine
PPAR delta
Fibroblast
PPAR-beta
Molecular Biology
Colorectal Cancer
chemistry.chemical_classification
Reactive oxygen species
Epithelial Cells
Fibroblasts
Science::Biological sciences [DRNTU]
Tumor Burden
030104 developmental biology
medicine.anatomical_structure
chemistry
Cancer research
Peroxisome proliferator-activated receptor delta
Reactive Oxygen Species
Carcinogenesis
Immortalised cell line
Oxidative stress
Zdroj: Oncogene
Oncogene, Nature Publishing Group, 2018, ⟨10.1038/s41388-017-0109-8⟩
Oncogene, . (2018)
Oncogene, vol. 37, no. 15, pp. 2067-2078
ISSN: 1476-5594
0950-9232
DOI: 10.1038/s41388-017-0109-8
Popis: 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/d fl/fl mice. The pre-treatment of FSPCre-Pparb/d -/- and Pparb/d fl/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/d fl/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.
Databáze: OpenAIRE
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