title: Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential.
abstract: The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with < 1% of cells displaying detectable nuclear localisation of plakoglobin. siRNA knockdown experiments targeting plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of E-cadherin expression. In bladder cell lines expressing low levels of plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with plakoglobin expression in the bladder model. These results show that plakoglobin acts as a tumour suppressor gene in bladder carcinoma cells and the silencing of plakoglobin gene expression in late-stage bladder cancer is a primary event in tumour progression.
authors.affiliation: Cell and Molecular Biology Laboratory, Robert E Wise MD Research and Education Institute, 31 Mall Road, Burlington, MA 01805, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Rieger-Christ
authors.forename: L
authors.initials: L
authors.lastname: Ng
authors.forename: R S
authors.initials: RS
authors.lastname: Hanley
authors.forename: O
authors.initials: O
authors.lastname: Durrani
authors.forename: H
authors.initials: H
authors.lastname: Ma
authors.forename: A S
authors.initials: AS
authors.lastname: Yee
authors.forename: J A
authors.initials: JA
authors.lastname: Libertino
authors.forename: I C
authors.initials: IC
authors.lastname: Summerhayes
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics*; D051301:Desmoglein 2; D051182:Desmogleins; D051180:Desmoplakins; D018450:Disease Progression; D015536:Down-Regulation; D015870:Gene Expression; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D023421:Models, Animal; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009367:Neoplasm Staging; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins; D051185:gamma Catenin
chemical_list: D015820:Cadherins; D003598:Cytoskeletal Proteins; C495314:DSG2 protein, human; D051301:Desmoglein 2; D051182:Desmogleins; D051180:Desmoplakins; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051185:gamma Catenin