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Title: The role of transmembrane mucin protein MUC1 in anoikis and in EGFR activation of human epithelial cancer cells
Author: Tushar, Piyush
ISNI:       0000 0004 7428 5969
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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MUC1 is a large, heavily glycosylated transmembrane mucin protein expressed on the apical membrane of normal epithelial cells. In epithelial cancer cells, however, MUC1 is overexpressed, abnormally glycosylated and loses its apical polarization, becoming expressed over the entire cell surface. Galectin-3, a β-galactoside-binding protein expressed by many types of human cells, is a natural ligand for MUC1. Recent studies by ourselves and others have revealed that the interaction between galectin-3 and MUC1 induces MUC1 cell surface polarization and the exposure of underlying smaller cell surface adhesion molecules. This leads to increased cancer cell homotypic aggregation and cancer cell (heterotypic) adhesion to vascular endothelium. Recently, mucin-1 (MUC1) was reported to be associated with epidermal growth factor receptor (EGFR) in epithelial cells. EGFR is a receptor tyrosine kinase involved in the regulation of multiple cellular process, including tumour proliferation and metastasis. Changes in MUC1, galectin-3 and EGFR expression have all, individually or in combination, been associated with poor cancer prognosis and increased tumour metastasis. Resistance of cancer cells to anoikis, a fundamental cellular process for maintaining tissue homeostasis, is a pre-requisite for metastasis. The aim of this study was to investigate the impact of MUC1 expression and the MUC1 interaction with galectin-3 and EGFR on EGFR activation and anoikis in epithelial cancer cells. It was found in this study, that overexpression of MUC1 in epithelial cells prevents initiation of anoikis in response to loss of adhesion. This effect was found to be attributed to both MUC1 extracellular and intracellular domains with predominant effect from the MUC1 extracellular domain. Reduction of MUC1 O-glycosylation by stable shRNA suppression of core 1 gal-transferase (C1GT) reduced MUC1-mediated resistance to anoikis in human colon cancer cells HCT116 and SW620. It was also found that MUC1 expression enhanced EGF-induced EGFR activation in human breast and colon cancer cells. Both the MUC1 extracellular and intracellular domains contribute to EGFR activation, again with the predominant contribution from the MUC1 extracellular domain. Thus, binding of galectin-3 to the MUC1 extracellular domain induces MUC1 cell surface polarization and increases MUC1-EGFR interaction, leading to increased EGFR homo-/hetero-dimerization and activation. These discoveries provide insight into the impact of MUC1 overexpression and MUC1 O-glycosylation on cancer cell behaviour in cancer progression and metastasis and may aid future development of novel therapeutic strategies for cancer treatment.
Supervisor: Yu, L. G. ; Rhodes, Jon Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral