Sequential down-regulation of E-cadherin with squamous cell carcinoma progression: loss of E-cadherin via a prostaglandin E2-EP2 dependent posttranslational mechanism.
The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E2 (PGE2) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE2 synthesis was enhanced. Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation. In contrast, addition of PGE2 or the EP2 receptor agonist butaprost to PMK produced a dose- and time-dependent decrease in E-cadherin. We also show that UV irradiation, via the PGE2-EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating E-cadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE2-EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers.
Brouxhon
Sabine
S
Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. Sabine_Brouxhon@urmc.rochester.edu
Kyrkanides
Stephanos
S
O'Banion
M Kerry
MK
Johnson
Renee
R
Pearce
David A
DA
Centola
Gina M
GM
Miller
Jen-nie H
JN
McGrath
Kieran H
KH
Erdle
Brandon
B
Scott
Glynis
G
Schneider
Sandra
S
VanBuskirk
JoAnne
J
Pentland
Alice P
AP
D000818:Animals; D015820:Cadherins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014466:Ultraviolet Rays
D015820:Cadherins; C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D046988:Proteasome Endopeptidase Complex; D015232:Dinoprostone