Role of MUC1 in idiopathic pulmonary fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible form of fibrotic intersticial lung disease, characterized by uncontrolled fibroblast proliferative processes and alveolar type II epithelial dysfunction. MUC1 is considered as oncogenic molecule by altering signaling pathways involved in cellular proliferation and cell death. Objective: To analyze the implication of MUC1 in IPF Methods: Lung tissue from 14 healthy and 14 IPF patients was obtained. The expression of MUC1 cytoplasmic tail (CT) and its phosphorylation forms in T-1224 and Y-1229 residues were analyzed by western blot and immunohistochemistry. The effect of MUC1 on TGFβ1-Iinduced epithelial to mesenchymal transition (EMT) and fibroblast to myofibroblast transition (FMT) was determined in alveolar type II A549 and fibrobast silenced with siRNA-MUC1. Results: MUC1-CT protein and mRNA expression were increased in lung tissue of IPF patients and mainly located in hyperplasic alveolar type II cells and fibrotic foci areas. T-1224 and Y-1229 phosphorylated forms of MUC1-CT were increased in IPF and undetected in healthy subjects. TGFβ1 promoted EMT by increasing alpha smooth muscle actin, collagen type I, SLUG and SNAIL, and decreasing E-cadherin expression only in wild type cells but not in siRNA-MUC1 cells. Similar results were observed in the TGFβ1-induced FTM process. TGFβ1 induced a MUC1-CT-T-1224 phosphorylation that was necessary to promote Smad3 and ERK1/2 phosphorylations and cellular transformations. Conclusions: MUC1-CT is increased and activated in lung tissue of IPF patients and collaborates with TGFβ1 to induce EMT and FMT cellular transformations. Pharmacologic targeting of MUC-CT may be a promising option for the treatment of IPF.