MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway

Abstract

Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-β1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-β1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-β1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF.

Carbohydrate antigen 125 on epicardial fat and its association with local inflammation and fibrosis-related markers

“…Current evidence supports that CA125 plays an active role in promoting epithelial to mesenchymal transition, a biological process allowing polarized, immobile epithelial cells to undergo biochemical changes that enable them to assume a mesenchymal cell phenotype [ 1 , 11 ]. This change results in increased migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly enhanced production of extracellular matrix components [ 1 ].…”

“…These epicardial-released adipokines have been associated with fibroblast proliferation, collagen synthesis, and myofibroblast activation [ 10 ]. Given that MUC16 can potentially be expressed in all mesothelial cells (including epicardium) and it is known to participate in modulating key fibrotic cellular processes such as epithelial-mesenchymal transition (EMT), fibroblast to myofibroblast transition, and fibroblast proliferation [ 1 , 11 ], we speculate that epicardial MUC16 could be associated with inflammatory and fibrotic processes in the human heart.…”

Mammalian Neuraminidases in Immune-Mediated Diseases: Mucins and Beyond

“…These apparent discrepant results might be explained, in part, by differences in disease etiologies, patient demographics, and/or lung sampling techniques between the various studies ( 201 , 203 , 204 ). The expression levels of MUC4 and MUC16 were elevated in patients with IPF, with evidence for each MUC4 and MUC16 promoting the fibrotic process in collaboration with TGF-β ( 206 – 209 ). Of particular prominence is a strong association of a gain-of-function MUC5B gene promoter variant (rs35705950) with pulmonary fibrosis ( 210 – 215 ).…”

The Role of Mesothelin in Activation of Portal Fibroblasts in Cholestatic Liver Injury

“…Studies of human ovarian cancer have revealed that the cancer antigen CA125 can serve as a ligand of MSLN [ 76 , 77 ], and co-expression of MUC16 and MSLN is known to be associated with the invasion process of cancers [ 78 , 79 , 80 , 81 ], with MUC16 promoting the potential role of MSLN in tumor adhesion, and metastasis [ 76 , 82 ]. CA125 is widely accepted as a diagnostic marker of ovarian cancer and a number of other malignant conditions such as breast cancer, mesothelioma, non-Hodgkin lymphoma, pancreatic cancer, gastric cancer, and leiomyoma [ 83 ], with exemption of benign conditions including endometriosis, pregnancy, congestive heart failure, nephrotic syndrome, and fibrosis-associated disease including liver cirrhosis and pulmonary fibrosis [ 84 , 85 , 86 , 87 , 88 ]. Muc16 as well as Msln were identified as signature genes of aPFs isolated from mouse BDL liver [ 8 ], and Muc16 was shown to bind to Msln as the ligand, facilitating the TGFβ receptor-mediated activation cascade of PFs in cholestatic injury [ 14 ].…”