Table 3.
Summarizes the main roles of the major lung mucins in IPF.
| Mucin | Participation in IPF |
|---|---|
| Secreted Mucins-Gel-Forming | |
| MUC5B | Expression 14.1 higher in IPF patients than in control subjects [20]. rs35705950: risk allele for IPF development (30%–35% of IPF patients) [20]. rs35705950: survival advantage allele [56]. |
| MUC5AC | Reduced expression in globet cells from IPF lesions in comparison with controls [57,58]. rs34474233 and rs34815853: risk alleles for IPF development. |
| Transmembrane Mucins | |
| MUC1 | Overexpression in lung tissue from IPF patients [59]. Secreted KL-6 1/MUC1 is proposed as a useful biomarker to evaluate disease activity and predict the clinical outcomes in IPF [10]. Secreted MUC1/KL-6 promotes lung fibroblast migration, proliferation, EMT 2 and FMT 3 [13,14]. MUC1 is activated by the extracellular endothelial ICAM-1 4 [60], elevated in serum of IPF patients [61]. MUC1-C terminal subunit interacts with the fibrotic galectin-3, serving as a bridge to associate MUC1-C with cell surface growth receptors involved in IPF [62]. Cell surface growth factor receptors involved in IPF (such as EGFR 5, FGFR3 6, PDGFR 7 and TGβR 8) phosphorylate and activate MUC1-CT 9 [63,64]. MUC1-CT is phosphorylated and activated by intracellular kinases such as c-Src, Lyn and Lck, which are activated by growth factors elevated in IPF [65] MUC1-CT interacts with the fibrotic transcription factor β-catenin and they both together translocate into the nucleus [64] MUC1-CT nuclear translocation promotes fibrotic processes [63]. |
| MUC4 | MUC4 is overexpressed in lung tissue from IPF patients [66]. MUC4 collaborates with the fibrotic TGFβ1 to induce EMT and FMT cellular transformations [66]. MUC4 induces nuclear translocation of the fibrotic transcription factor β-catenin [67]. MUC4 serves as an intramembrane ligand for ErbB2, inducing activation of ERK ½ 10 and regulating cell proliferation, growth, survival and differentiation [68]. |
| MUC16 | MUC16/CA125 antigen has been identified as a serum biomarker to predict disease progression and death in IPF patients [8]. MUC16-C terminal subunit associates with JAK2 11 and promotes cell proliferation [69]. MUC16-C terminal subunit decreases TRAIL 12-induced apoptosis [70]. MUC16 interacts with c-Src and the E-cadherin/β-catenin complex, leading to deregulation of E-Cadherin and enhancing cell migration [71]. MUC16 binds to mesothelin, enhancing epithelial mesothelial to mesenchymal transition, cell motility and invasion [42]. MUC16 binds to galectin-1 [72] and galectin-3 [73]. |
1 KL-6: Krebs von den Lungen-6; 2 EMT: epithelial to mesenchymal transition; 3 FMT: fibroblast to mesenchymal transition; 4 ICAM-1: intercellular adhesion molecule 1; 5 EGFR: epidermal growth factor receptor; 6 FGFR3: fibroblast growth factor receptor 3; 7 PDGFR: platelet derived growth factor receptor; 8 TGβR: transforming growth factor β receptor; 9 MUC1-CT: MUC1-cytoplasmic tail; 10 ERK1/2: extracellular signal-regulated kinase 1/2; 11 JAK2: Janus kinase 2; 12 TRAIL: TNF-related apoptosis-inducing ligand.