title: Estrogen stimulates the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway and regulation of its downstream targets E‑cadherin and α‑actinin‑4.
abstract: Previous studies by our group revealed that the phosphoinositide 3‑kinase (PI3K)/AKT pathway was involved in estrogen‑induced metastasis in ovarian cancer cells. In the present study, the role and mechanism of estrogen‑induced invasion was further explored using a stable short hairpin RNA (shRNA) estrogen receptor α/β (ER α/β) SKOV3 cell line when ER α and ER β were knocked down by lentiviral infection. The effects of estrogen and LY294002, a PI3K inhibitor, on the invasion of shRNA ER α/β SKOV3 cells were evaluated in vitro and in vivo. 17‑β estradiol promoted cell invasion, activated phosphorylated AKT in a dose‑ and time‑dependent manner, decreased E‑cadherin and increased cytoplasmic α‑actinin‑4 expression. When the PI3K/AKT pathway was suppressed by LY294002, the effect of estrogen was attenuated. Estrogen stimulated the growth of shRNA ER α/β SKOV3 xenograft tumors in nude mice, whereas LY294002 inhibited the growth and antagonized the effect of estrogen. The results indicate that estrogen promotes the invasion of ovarian cancer cells via activation of the PI3K/AKT pathway, downregulation of E‑cadherin and upregulation of α‑actinin‑4 in an ER‑independent manner. Inhibiting the PI3K/AKT pathway may be a useful treatment for ovarian carcinoma.
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Yisong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Tao
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jia
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Lyu
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Jingxin
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Gynecology, The Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
authors.forename: Keqin
authors.initials: K
authors.lastname: Hua
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004967:Estrogens / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C111453:ACTN4 protein, human; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D004967:Estrogens; D000185:Actinin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt