title: MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition.
abstract: Increased motility and invasiveness of pancreatic cancer cells are associated with epithelial to mesenchymal transition (EMT). Snai1 and Slug are zinc-finger transcription factors that trigger this process by repressing E-cadherin and enhancing vimentin and N-cadherin protein expression. However, the mechanisms that regulate this activation in pancreatic tumors remain elusive. MUC1, a transmembrane mucin glycoprotein, is associated with the most invasive forms of pancreatic ductal adenocarcinomas (PDA). In this study, we show that over expression of MUC1 in pancreatic cancer cells triggers the molecular process of EMT, which translates to increased invasiveness and metastasis. EMT was significantly reduced when MUC1 was genetically deleted in a mouse model of PDA or when all seven tyrosines in the cytoplasmic tail of MUC1 were mutated to phenylalanine (mutated MUC1 CT). Using proteomics, RT-PCR and western blotting, we revealed a significant increase in vimentin, Slug and Snail expression with repression of E-Cadherin in MUC1-expressing cells compared with cells expressing the mutated MUC1 CT. In the cells that carried the mutated MUC1 CT, MUC1 failed to co-immunoprecipitate with β-catenin and translocate to the nucleus, thereby blocking transcription of the genes associated with EMT and metastasis. Thus, functional tyrosines are critical in stimulating the interactions between MUC1 and β-catenin and their nuclear translocation to initiate the process of EMT. This study signifies the oncogenic role of MUC1 CT and is the first to identify a direct role of the MUC1 in initiating EMT during pancreatic cancer. The data may have implications in future design of MUC1-targeted therapies for pancreatic cancer.
authors.affiliation: Department of Biology, University of North Carolina Charlotte, Charlotte, NC 28223, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Roy
authors.forename: M
authors.initials: M
authors.lastname: Sahraei
authors.forename: D B
authors.initials: DB
authors.lastname: Subramani
authors.forename: D
authors.initials: D
authors.lastname: Besmer
authors.forename: S
authors.initials: S
authors.lastname: Nath
authors.forename: T L
authors.initials: TL
authors.lastname: Tinder
authors.forename: E
authors.initials: E
authors.lastname: Bajaj
authors.forename: K
authors.initials: K
authors.lastname: Shanmugam
authors.forename: Y Y
authors.initials: YY
authors.lastname: Lee
authors.forename: S I L
authors.initials: SI
authors.lastname: Hwang
authors.forename: S J
authors.initials: SJ
authors.lastname: Gendler
authors.forename: P
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C060192:MUC1 protein, human; D018396:Mucin-1; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014443:Tyrosine