β-Catenin determines upper airway progenitor cell fate and preinvasive squamous lung cancer progression by modulating epithelial-mesenchymal transition

TY - JOUR

T1 - β-Catenin determines upper airway progenitor cell fate and preinvasive squamous lung cancer progression by modulating epithelial-mesenchymal transition

AU - Giangreco, Adam

AU - Lu, Liwen

AU - Vickers, Charles

AU - Teixeira, Vitor Hugo

AU - Groot, Karen R.

AU - Butler, Colin R.

AU - Ilieva, Ekaterina V.

AU - George, P. Jeremy

AU - Nicholson, Andrew G.

AU - Sage, Elizabeth K.

AU - Watt, Fiona M.

AU - Janes, Sam M.

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Human lung cancers, including squamous cell carcinoma (SCC) are a leading cause of death and, whilst evidence suggests that basal stem cells drive SCC initiation and progression, the mechanisms regulating these processes remain unknown. In this study we show that β-catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell β-catenin signalling is positively associated with increased disease severity, epithelial proliferation and reduced intercellular adhesiveness. We demonstrate that transgene-mediated β-catenin inhibition within keratin 14-expressing basal cells delayed normal airway repair while basal cell-specific β-catenin activation increased cell proliferation, directed differentiation and promoted elements of early epithelial-mesenchymal transition (EMT), including increased Snail transcription and reduced E-cadherin expression. These observations are recapitulated in normal human bronchial epithelial cells in vitro following both pharmacological β-catenin activation and E-cadherin inhibition, and mirrored our findings in preinvasive SCCs. Overall, the data show that airway basal cell β-catenin determines cell fate and its mis-expression is associated with the development of human lung cancer.

AB - Human lung cancers, including squamous cell carcinoma (SCC) are a leading cause of death and, whilst evidence suggests that basal stem cells drive SCC initiation and progression, the mechanisms regulating these processes remain unknown. In this study we show that β-catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell β-catenin signalling is positively associated with increased disease severity, epithelial proliferation and reduced intercellular adhesiveness. We demonstrate that transgene-mediated β-catenin inhibition within keratin 14-expressing basal cells delayed normal airway repair while basal cell-specific β-catenin activation increased cell proliferation, directed differentiation and promoted elements of early epithelial-mesenchymal transition (EMT), including increased Snail transcription and reduced E-cadherin expression. These observations are recapitulated in normal human bronchial epithelial cells in vitro following both pharmacological β-catenin activation and E-cadherin inhibition, and mirrored our findings in preinvasive SCCs. Overall, the data show that airway basal cell β-catenin determines cell fate and its mis-expression is associated with the development of human lung cancer.

KW - airway

KW - E-cadherin

KW - lung cancer

KW - pre-invasive

KW - Snail

KW - squamous

KW - stem cell

KW - β-catenin

UR - http://www.scopus.com/inward/record.url?scp=84856692365&partnerID=8YFLogxK

U2 - 10.1002/path.3962

DO - 10.1002/path.3962

M3 - Article

C2 - 22081448

SN - 0022-3417

VL - 226

SP - 575

EP - 587

JO - Journal of pathology

JF - Journal of pathology

IS - 4

ER -