Olfactomedin-4 regulation by estrogen in the human endometrium requires epidermal growth factor signaling.
Olfactomedin-4 (OLFM-4) is an extracellular matrix protein that is highly expressed in human endometrium. We have examined the regulation and function of OLFM-4 in normal endometrium and in cases of endometriosis and endometrial cancer. OLFM-4 expression levels are highest in proliferative-phase endometrium, and 17β-estradiol up-regulates OLFM-4 mRNA in endometrial explant cultures. Using the luciferase reporter under control of the OLFM-4 promoter, it was shown that both 17β-estradiol and OH-tamoxifen induce luciferase activity, and epidermal growth factor receptor-1 is required for this estrogenic response. In turn, EGF activates the OLFM-4 promoter, and estrogen receptor-α is needed for the complete EGF response. The cellular functions of OLFM-4 were examined by its expression in OLFM-4-negative HEK-293 cells, which resulted in decreased vimentin expression and cell adherence as well as increased apoptosis resistance. In cases of endometriosis and endometrial cancer, OLFM-4 expression correlated with the presence of epidermal growth factor receptor-1 and estrogen receptor-α (or estrogen signaling). An increase of OLFM-4 mRNA was observed in the endometrium of endometriosis patients. No change in OLFM-4 expression levels were observed in patients with endometrial cancer relative with controls. In conclusion, cross-talk between estrogen and EGF signaling regulates OLFM-4 expression. The role of OLFM-4 in endometrial tissue remodeling before the secretory phase and during the predisposition and early events in endometriosis can be postulated but requires additional investigation.
GROW--School for Oncology and Developmental Biology, Department of Pathology, Maastricht University and Medical Centre, 6202 AZ, Maastricht, The Netherlands.
Hellen
H
Dassen
Chamindie
C
Punyadeera
Bert
B
Delvoux
Iris
I
Schulkens
Claudia
C
Marchetti
Rick
R
Kamps
Jan
J
Klomp
Fred
F
Dijcks
Anton
A
de Goeij
Thomas
T
D'Hooghe
Cleophas
C
Kyama
Antwan
A
Ederveen
Gerard
G
Dunselman
Patrick
P
Groothuis
Andrea
A
Romano
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002448:Cell Adhesion; D002478:Cells, Cultured; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology; D004715:Endometriosis / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008597:Menstrual Cycle / Q000502:physiology; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000502:physiology*; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D004967:Estrogens; C454127:OLFM4 protein, human; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D014746:Vimentin; D016179:Granulocyte Colony-Stimulating Factor; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors