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

2017; Impact Journals LLC; Volume: 8; Issue: 52 Linguagem: Inglês

10.18632/oncotarget.21234

1949-2553

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

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

// Alexandre Vallée 1, 2 , Yves Lecarpentier 3 , Rémy Guillevin 4 and Jean-Noël Vallée 2, 5 1 Experimental and Clinical Neurosciences Laboratory, INSERM U1084, University of Poitiers, Poitiers, France 2 Laboratory of Mathematics and Applications (LMA), UMR CNRS 7348, University of Poitiers, Poitiers, France 3 Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France 4 DACTIM, UMR CNRS 7348, University of Poitiers et CHU de Poitiers, Poitiers, France 5 CHU Amiens Picardie, University of Picardie Jules Verne (UPJV), Amiens, France Correspondence to: Alexandre Vallée, email: alexandre.g.vallee@gmail.com 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 ABSTRACT 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.