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

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.

The role of WNT10B in normal prostate gland development and prostate cancer

“…TGFβ1 in normal conditions inhibits cell growth, promotes differentiation, and induces apoptosis . Further, TGFβ1 and canonical WNT signaling have been reported to stimulate each other through Smad and non‐Smad pathways . As such, the loss of the antiproliferative WNT10B effects in localized PCa may be, in part, mediated through downregulation of TGFβ1.…”

“…[44][45][46] Further, TGFβ1 and canonical WNT signaling have been reported to stimulate each other through Smad and non-Smad pathways. 47 As such, the loss of the antiproliferative WNT10B effects in localized PCa may be, in part, mediated through downregulation of TGFβ1. However, TGFβ1 is also known to be a primary inducer of EMT 48 which underscores its role as a driver of aggressive disease.…”

PPAR‐γ signalling as a key mediator of human hair follicle physiology and pathology

“…[16] This gene encodes the alpha 1 chain of collagen VI, which is expressed in the bulge area of the HF and is involved in the development of the HF during embryogenesis, where it is postulated to inhibit Wnt/β-catenin signalling. [74][75][76][77][78] Wnt/β-catenin signalling is essential for normal human HF function [79][80][81] and for stem cell maintenance [82] ; however, it is Selective PPAR-γ receptor modulators may exert antagonistic or agonistic effects, according to the cell type they function in, and act by modulating the cofactor affinity resulting in changes in the transcriptional activation. This is in contrast to full PPAR-γ agonists that lead to the release of the co-repressor complex and co-activator binding, and PPAR-γ antagonists that result in inadequate conformational modulation of the receptor and preventing the connection with the co-activator.…”

The Smad2/3/4 complex binds miR‐139 promoter to modulate TGFβ‐induced proliferation and activation of human Tenon's capsule fibroblasts through the Wnt pathway

“…Interestingly, when Smad2, 3, and 4 were cotransfected, the luciferase activity of wt-miR-139 was more suppressed although more reversed after the mutation of the predicted Smad4-binding site (Figure 5d It has been reported that miR-139 plays a role in the fibrosis process. MiR-139 can target a series of crucial factors in Wnt signaling, which is an essential signaling pathway in TGFβ1-induced fibrosis (Vallée, Lecarpentier, Guillevin, & Vallée, 2017). In human fibroblast IMR-90 and murine lung fibroblasts, miR-139 interference remarkably increased the expression of β-catenin, collagen I, and α-SMA, indicating that miR-139 inhibition promotes the activation of fibroblasts (Y.…”