Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis

Alexandre Vallée _, Yves Lecarpentier, Rémy Guillevin and Jean-Noël Vallée

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Oncotarget. 2017; 8:90579-90604. https://doi.org/10.18632/oncotarget.21234

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Alexandre Vallée1,2, Yves Lecarpentier3, Rémy Guillevin4 and Jean-Noël Vallée2,5

1Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France

2Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France

3Centre de Recherche Clinique, Grand Hôpital de l’Est Francilien (GHEF), Meaux, France

4DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France

5CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France

Correspondence to:

Alexandre Vallée, email: [email protected]

Keywords: TGF-β, canonical WNT/β-catenin pathway, PPAR γ, radiation-induced fibrosis, myofibroblast

Received: June 16, 2017     Accepted: August 17, 2017     Published: September 23, 2017


Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease radiation-induced fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote radiation-induced fibrosis whereas PPAR γ agonists can prevent radiation-induced fibrosis.

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