Pivotal role of MUC1 glycosylation by cigarette smoke in modulating disruption of airway adherens junctions in vitro

被引:39
|
作者
Zhang, Lili [1 ]
Gallup, Marianne [1 ]
Zlock, Lorna [2 ]
Chen, Yu Ting Feeling [1 ]
Finkbeiner, Walter E. [2 ]
McNamara, Nancy A. [1 ,3 ,4 ,5 ,6 ]
机构
[1] Univ Calif San Francisco, Francis I Proctor Fdn, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA
[3] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA USA
[5] Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA
[6] Univ Calif Berkeley, Vis Sci Grad Program, Berkeley, CA 94720 USA
来源
JOURNAL OF PATHOLOGY | 2014年 / 234卷 / 01期
关键词
p120-catenin; MUC1; glycosylation; E-cadherin; EGFR; galectin-3; in vitro airway model; epithelial-mesenchymal transition; cigarette smoke; lung cancer; EPITHELIAL-MESENCHYMAL TRANSITION; N-ACETYLGALACTOSAMINYLTRANSFERASE; 6; CELL LUNG-CANCER; O-GLYCOSYLATION; EXPRESSION; MUCINS; CARCINOMA; CATENIN; P120-CATENIN; PROGNOSIS;
D O I
10.1002/path.4375
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cigarette smoke increases the risk of lung cancer by 20-fold and accounts for 87% of lung cancer deaths. In the normal airway, heavily O-glycosylated mucin-1 (MUC1) and adherens junctions (AJs) establish a structural barrier that protects the airway from infectious, inflammatory and noxious stimuli. Smoke disrupts cell-cell adhesion via its damaging effects on the AJ protein epithelial cadherin (E-cad). Loss of E-cad is a major hallmark of epithelial-mesenchymal transition (EMT) and has been reported in lung cancer, where it is associated with invasion, metastasis and poor prognosis. Using organotypic cultures of primary human bronchial epithelial (HBE) cells treated with smoke-concentrated medium (Smk), we have demonstrated that E-cad loss is regulated through the aberrant interaction of its AJ binding partner, p120-catenin (p120ctn), and the C-terminus of MUC1 (MUC1-C). Here, we reported that even before MUC1-C became bound to p120ctn, smoke promoted the generation of a novel 400 kDa glycoform of MUC1's N-terminus (MUC1-N) differing from the 230 kDa and 150 kDa glycoforms in untreated control cells. The subsequent smoke-induced, time-dependent shedding of glycosylated MUC1-N exposed MUC1-C as a putative receptor for interactions with EGFR, Src and p120ctn. Smoke-induced MUC1-C glycosylation modulated MUC1-C tyrosine phosphorylation (TyrP) that was essential for MUC1-C/p120ctn interaction through dose-dependent bridging of Src/MUC1-C/galectin-3/EGFR signalosomes. Chemical deglycosylation of MUC1 using a mixture of N-glycosylation inhibitor tunicamycin and O-glycosylation inhibitor benzyl-alpha-GalNAc disrupted the Src/MUC1-C/galectin-3/EGFR complexes and thereby abolished smoke-induced MUC1-C-TyrP and MUC1-C/p120ctn interaction. Similarly, inhibition of smoke-induced MUC1-N glycosylation using adenoviral shRNA directed against N-acetyl-galactosaminyl transferase-6 (GALNT6, an enzyme that controls the initiating step of O-glycosylation) successfully suppressed MUC1-C/p120ctn interaction, prevented E-cad degradation and maintained cellular polarity in response to smoke. Thus, GALNT6 shRNA represents a potential therapeutic modality to prevent the initiation of events associated with EMT in the smoker's airway. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:60 / 73
页数:14
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