MicroRNA-200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation.
Although cervical pregnancy and placenta previa, in which the embryo and placenta embed in or adjacent to the cervix, are life-threatening complications that result in massive bleeding and poor pregnancy outcomes in women, the incidence of these aberrant conditions is uncommon. We hypothesized that a local molecular mechanism is normally in place to prevent embryo implantation in the cervix. The ovarian hormones progesterone (P(4)) and estrogen differentially direct differentiation and proliferation of endometrial cells, which confers the receptive state for implantation: P(4) dominance causes differentiation of the luminal epithelium but increases stromal cell proliferation in preparation of the uterus for implantation. In search for the cause of cervical nonresponsiveness to implantation, we found that the statuses of cell proliferation and differentiation between the uterus and cervix during early pregnancy are remarkably disparate under identical endocrine milieu in both mice and humans. We also found that cervical levels of progesterone receptor (PR) protein are low compared with uterine levels during this period, and the low PR protein levels are attributed to elevated levels of microRNA(miR)-200a in the cervix. These changes were associated with up-regulation of the P(4)-metabolizing enzyme 20α-hydroxysteroid dehydrogenase (200α-HSD) and down-regulation of its transcriptional repressor signal transducer and activator of transcription 5 in the cervix. The results provide evidence that elevated levels of miR-200a lead to down-regulation of P(4)-PR signaling and up-regulation of (200α-HSD) in the cervix, rendering it nonresponsive to implantation. These findings may point toward not only the physiological but also the pathological basis of the cervical milieu in embryo implantation.
Department of Obstetrics and Gynecology (H.H., T.S.-F., Y.H., M.E., L.M., M.M., T.H., K.K., T.F., Y.O.) and Department of Pathology (N.Y., M.F.), Graduate School of Medicine; Department of Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences (M.E.); the University of Tokyo, Tokyo 113-8655, Japan; Precursory Research for Embryonic Science and Technology (Y.H.), Japan Science and Technology Agency, Saitama 332-0012, Japan; and Division of Reproductive Sciences (A.B., J.C., S.K.D.), Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, Ohio 45229.
Hirofumi
H
Haraguchi
Tomoko
T
Saito-Fujita
Yasushi
Y
Hirota
Mahiro
M
Egashira
Leona
L
Matsumoto
Mitsunori
M
Matsuo
Takehiro
T
Hiraoka
Kaori
K
Koga
Naoko
N
Yamauchi
Masashi
M
Fukayama
Amanda
A
Bartos
Jeeyeon
J
Cha
Sudhansu K
SK
Dey
Tomoyuki
T
Fujii
Yutaka
Y
Osuga
D043607:20-alpha-Hydroxysteroid Dehydrogenase / Q000096:biosynthesis*; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002584:Cervix Uteri / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D010064:Embryo Implantation / Q000235:genetics; D010065:Embryo Implantation, Delayed / Q000235:genetics*; D004717:Endometrium / Q000166:cytology / Q000254:growth & development; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D015735:Mifepristone / Q000494:pharmacology; D011247:Pregnancy; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000096:biosynthesis; D017154:Stromal Cells / Q000166:cytology; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D015854:Up-Regulation; D014599:Uterus / Q000502:physiology
D004967:Estrogens; D019394:Ki-67 Antigen; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D011980:Receptors, Progesterone; D050799:STAT5 Transcription Factor; D015735:Mifepristone; D011374:Progesterone; D043607:20-alpha-Hydroxysteroid Dehydrogenase; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4