title: An aberrant nuclear localization of E-cadherin is a potent inhibitor of Wnt/β-catenin-elicited promotion of the cancer stem cell phenotype.
abstract: Several studies suggest that Wnt signaling contributes to reprogramming and maintenance of cancer stem cell (CSC) states activated by loss of membranous E-cadherin expression. However, E-cadherin's exact role in Wnt/β-catenin-mediated promotion of the CSC phenotype remains unclear. Recently, a significant positive correlation has been observed between the expression of nuclear (an aberrant nuclear localization) E-cadherin and β-catenin in gastric and colorectal carcinomas. Here we conducted a series of in-vitro and in-vivo studies to show that the β-catenin/TCF4 interaction was abolished by E-cadherin and was correlated with its nuclear localization, and consequently decreased β-catenin/TCF4 transcriptional activity. Nuclear E-cadherin was a negative regulator of Wnt/β-Catenin-elicited promotion of the CSC phenotype. Using immunohistochemistry on lung cancer tissue microarrays, we found that changes in subcellular location of E-cadherin may be described by tumor grade and stage, suggesting cellular redistribution during lung tumorigenesis. Furthermore, nuclear E-cadherin expression was more significantly inversely correlated with CD133 (a lung CSC marker) expression (P<0.005) than total E-cadherin expression (P<0.05), suggesting that lung cancer as defined by nuclear E-cadherin(Low)/nuclear β-catenin(High)/CD133(High) biomarkers has superior prognostic value over total E-cadherin(Low)/nuclear β-catenin(High)/CD133(High).
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Su
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Chang
authors.affiliation: 1] Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan [2] Department of Orthopedics, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
authors.forename: W-H
authors.initials: WH
authors.lastname: Lin
authors.affiliation: Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Liang
authors.affiliation: 1] Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan [2] Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: J-L
authors.initials: JL
authors.lastname: Lee