17β-Estradiol Induces Overproliferation in Adenomyotic Human Uterine Smooth Muscle Cells of the Junctional Zone Through Hyperactivation of the Estrogen Receptor-Enhanced RhoA/ROCK Signaling Pathway.
Adenomyosis (ADS) is a common estrogen-dependent gynecological disease with unknown etiology. Recent models favor abnormal thickening of the junctional zone (JZ) may be the causative factor in the development of ADS. RhoA, a small guanosine triphosphatase which controls multiple cellular processes, is involved in the control of cell proliferation. Here we demonstrate that treatment of human uterine smooth muscle cells (SMCs) of the JZ with 17β-estradiol (E2) increased expression of RhoA and its downstream effectors (-associated coiled coil containing protein kinase [ROCK] 1 and ROCK2). Compared with non-ADS cells, RhoA, ROCK1, and ROCK2 were overexpressed and hyperactivated in ADS cells. These effects were suppressed in the presence of ICI 182,780, supporting an estrogen receptor (ER)-dependent mechanism. Hyperactivation of ER-enhanced RhoA/ROCK signaling was associated with overproliferation in ADS human uterine SMCs of the JZ. Moreover, E2-induced overproliferation was accompanied by downregulation of cyclin-dependent kinases inhibitors (CKIs; p21(Waf1/Cip1) and p27(Kip1)) and upregulation of cyclin-dependent kinases (CDKs) and cyclins (cyclin D1, cyclin E1, CDK2, CDK4, and CDK6).
Department of Gynecology, Minimally Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Fu-Qing
FQ
Sun
Department of Gynecology, Minimally Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China duanhuasci@163.com.
Hua
H
Duan
Department of Gynecology, Minimally Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Sha
S
Wang
Department of Gynecology, Minimally Invasive Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Jin-Jiao
JJ
Li
D062788:Adenomyosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009215:Myometrium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; C066737:RHOA protein, human; D004958:Estradiol; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
RhoA/ROCK pathway; adenomyosis; estradiol; junctional zone; proliferation