Deletion of prostaglandin E2 EP2 receptor protects against ultraviolet-induced carcinogenesis, but increases tumor aggressiveness.
Ultraviolet (UV) light is a complete carcinogen inducing and promoting squamous-cell carcinoma (SCC) of the skin. Recent work has shown that SCC initiation and promotion are enhanced by prostaglandin E2 (PGE2). PGE2 interacts with specific EP receptors to regulate cellular functions. Previous work from our group has shown that the prostaglandin E2 EP2 receptor is a powerful regulator of keratinocyte growth. SKH-1 hairless mice lacking the EP2 receptor were therefore studied to understand how this growth signaling pathway contributes to photocarcinogenesis. Our data indicate that UV-irradiated mice lacking EP2 receptors exhibit decreased proliferation and a poor capacity for epidermal hypertrophy in response to UV injury. In a chronic irradiation model, these animals were protected from tumor formation, developing 50% fewer tumors than wild-type controls. Despite this capacity to protect against tumorigenesis, animals lacking EP2 receptors grew tumors that were larger in size, with a more aggressive phenotype. Further study suggested that this susceptibility may be associated with synthesis of active metalloproteinase enzymes in greater quantities than keratinocytes expressing the EP2 receptor, thereby enhancing the invasive potential of EP2-/- cells.
Brouxhon
Sabine
S
Department of Emergency Medicine, University of Rochester School of Medicine & Dentistry, Rochester, New York, USA.
Konger
Raymond L
RL
VanBuskirk
JoAnne
J
Sheu
Tzong-jen
TJ
Ryan
Julie
J
Erdle
Brandon
B
Almudevar
Anthony
A
Breyer
Richard M
RM
Scott
Glynis
G
Pentland
Alice P
AP
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009381:Neoplasms, Radiation-Induced / Q000473:pathology / Q000517:prevention & control; D010641:Phenotype; D018078:Receptors, Prostaglandin E / Q000172:deficiency* / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology* / Q000517:prevention & control*; D014466:Ultraviolet Rays
C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D020782:Matrix Metalloproteinases