title: HIF-1α binding to AEG-1 promoter induced upregulated AEG-1 expression associated with metastasis in ovarian cancer.
abstract: Ovarian cancer with the highest mortality rate among gynecological malignancies is one of common cancers among female cancer patients. As reported in recent years, AEG-1 was associated with the occurrence, development, and metastasis of ovarian cancer, but the mechanisms remain unclear. In the current study, invasion capabilities of ovarian cancer OVCAR3 cells were measured by viral infection and transwell assay. Western blot analysis was used to evaluate the expression levels of β-catenin, E-cadherin, MMP2, and MMP9. With qRT-PCR analysis, AEG-1 and HIF-1α gene expression were detected. We used luciferase reporter gene to measure AEG-1 promoter activity under normoxia/hypoxia in OVCAR3 cells. Our work demonstrated that AEG-1 significantly enhanced invasion capabilities of OVCAR3 cells and the expression levels of β-catenin, E-cadherin, MMP2, and MMP9 associated with invasion capabilities of OVCAR3 cells were upregulated. Furthermore, hypoxia enhanced invasion capabilities of OVCAR3 cells and induced AEG-1 high gene expression, which was reversed by AEG-1 knockdown lentivirus. HIF-1α expression upregulation was induced in OVCAR3 cells after hypoxia. HIF-1α knockdown lentivirus induced downregulated expression of AEG-1 and invasion capabilities of OVCAR3 cells were also inhibited. Wild-type AEG-1 promoter activity under hypoxic conditions was significantly higher than that AEG-1 mutation under normoxic conditions in the absence of hypoxia response. Our results suggested that HIF-1α binds to AEG-1 promoter to upregulate its expression, which was correlated with metastasis in ovarian cancer by inducing the expression of MMP2 and MMP9 as well as inhibiting expression of E-cadherin and β-catenin.
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: Chenyan
authors.initials: C
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.affiliation: The Diagnosis and Treatment Center of Cervical Disease, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: Yuan
authors.identifier: http://orcid.org/0000-0002-2961-3770
authors.initials: Y
authors.lastname: Lu
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D051176:beta Catenin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: AEG-1; HIF-1α; OVCAR3 cells; metastasis; ovarian cancer