Cigarette Smoke Induces Epidermal Growth Factor Receptor-Dependent Redistribution of Apical MUC1 and Junctional β-Catenin in Polarized Human Airway Epithelial Cells

Abstract

Cigarette smoke (CS) accounts for nearly 90% of lung cancer deaths worldwide; however, an incomplete understanding of how CS initiates preneoplastic changes in the normal airway hinders early diagnosis. Short-term exposure to CS causes aberrant activation of epidermal growth factor receptor (EGFR) and canonical Wnt/␤-catenin signaling pathways in human bronchial epithelial (HBE) cells. We hypothesize that this response is elicited through the disruption of spatially segregated cell membrane proteins in the polarized airway epithelium. Using an in vitro model of highly differentiated HBE cells, we observed membrane characteristics consistent with the native airway, including the presence of a membrane mucin, MUC1, at the apical cell pole, ␤-catenin at the apicallateral membrane, and EGFR at the basolateral membrane. Following exposure to smoke, intercellular spaces enlarge and cilia disappear. This histopathology is accompanied by molecular events that include perinuclear trafficking of basolateral EGFR, EGFR phosphorylation, pEGFR-mediated phosphorylation of MUC1's cytoplasmic tail (CT), loss of E-cadherin/␤-catenin complexes at the adherens junctions (AJs), intracellular formation and nuclear shuffling of ␤-catenin/MUC1-CT complexes, and, ultimately, upregulation and nuclear localization of Wnt nuclear effector, Lef-1. In the presence of EGFR inhibitor, AG1478, CS-induced histopathology and molecular events were inhibited. These data point to EGFR as a portal through which CS mediates its damaging effects on AJ-mediated cell polarity and activation of canonical Wnt/␤-catenin signaling.

Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps

“…Similarly, previous findings showed that the MUC1-CT-ERa transcription complex protected and stabilized ERa by attenuating its ubiquitination and degradation, 16 and a protective role of b-catenin degradation by the b-catenin-MUC1-CT transcription complex was similarly proposed. 17 These findings are in line with a possible protective role of MUC1-CT on GRa.…”

“…16 Similar findings were observed for the b-catenin-MUC1-CT transcription complex as a modulator of morphogenesis. 17,18 Corticosteroids exert their anti-inflammatory functions by binding to their intracellular receptor, the glucocorticoid receptor (GR), which is a ligand-inducible transcription factor. In the absence of its ligand, GR resides predominantly in the cytoplasm, where it is sequestered in a multimeric chaperone complex comprising heat-shock protein (hsp) 90, hsp70, hsp90-binding protein p23, immunophilins, and other factors to prevent its degradation and assist in its maturation.…”

Innate Immunity in the Respiratory Epithelium

“…Activation of EGFR results in increased production of MUC5AC in the airway epithelium (196), and P. aeruginosa induces MUC5AC via activation of MAPK and EGFR (57,197,198). Increased mucin is a response to tobacco smoke (197), and EGFR serves as a gateway for cigarette smoke to mediate its damaging effects on adherens junctions and Wnt/ b-catenin signaling (199). TACE is an integral component of this response because inhibiting TACE prevents the increased mucin expression as a result of reduce TGF-a shedding (198) An interplay exists between EGFR signaling and the TLRs.…”

Innate Immunity of Airway Epithelium and COPD

“…Consistent with this notion, cigarette smoke in combination with IL-1 has been shown to induce disassembly of tight junction complex in endothelial cells by suppressing PTEN activity (Barbieri et al, 2008). Chen et al showed that cigarette smoke also alters epithelial permeability by disrupting cell polarity via activation of EGFR, dissociation of -catenin and E-cadherin from adherence junctional complex and redistribution of apical MUC1 membrane bound mucin to cytoplasm (Chen et al, 2010). In a homestatic epithelium, -catenin cooperates with E-cadherin to form apical junctional complex and maintain cell polarity (Xu and Kimelman, 2007).…”

“…In airway regeneration or oncogenic formation -catenin translocates to nucleus, and activates canonical Wnt signaling pathway (Mazieres et al, 2005;Tian et al, 2009). Similar to -catenin, the cytoplasmic tail of MUC1 also supports structural barrier during homeostasis (Chen et al, 2010). Since cigarette smoke causes aberrant activation of both EGFR and canonical Wnt/ -catenin signaling (Khan et al, 2008;Lemjabbar et al, 2003), it is plausible that chronic cigarette smoke exposure decreases barrier function and promote microbial invasion of airway epithelium.…”