title: Estrogen and ERα enhanced β-catenin degradation and suppressed its downstream target genes to block the metastatic function of HA22T hepatocellular carcinoma cells via modulating GSK-3β and β-TrCP expression.
abstract: In our previous experiments, we found β-catenin was highly expressed in the tumor area with high invasive ability and poor prognosis. In this study, we have examined the mechanism by which ERα regulates β-catenin expression as well as the metastasis ability of hepatocellular cancer HA22T cells. To identify whether the anticancer effect of estrogen and ERα is mediated through suppression of β-catenin expression, we co-transfected pCMV-β-catenin and ERα into HA22T cells, and determined the cell motility by wound healing, invasion, and migration assays. Results showed that estrogen and/or ERα inhibited β-catenin gene expression and repressed HA22T cell motility demonstrated that similar data was observed in cells expressing the ERα stable clone. Moreover, we examined the protein-protein interaction between ERα and β-catenin by immunostain, co-immunoprecipitation, and Western blotting. E2 enhanced the binding of ERα with β-catenin and then triggered β-catenin to bind with E3 ligase (βTrCP) to promote β-catenin degradation. Finally by employing systematic ChIP studies, we showed ERα can interact directly with the β-catenin promoter region following E2 treatment. All our results reveal that estrogen and ERα blocked metastatic function of HA22T cells by modulating GSK3β and βTrCP expression and further enhanced β-catenin degradation and suppressed its downstream target genes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 519-529, 2017.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Section of Cardiology, Yuan Rung Hospital, Yuanlin, Taiwan.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Bharath Kumar
authors.initials: BK
authors.lastname: Velmurugan
authors.affiliation: Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Hwai-Lee
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Chest Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan.
authors.forename: Chuan-Chou
authors.initials: CC
authors.lastname: Tu
authors.affiliation: Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ray-Jade
authors.initials: RJ
authors.lastname: Che
authors.affiliation: Division of Colorectal Surgery, Veterans General Hospital, Taichung, Taiwan.
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Long-Bin
authors.initials: LB
authors.lastname: Jen
authors.affiliation: Department of Biotechnology, Bharathiar University, Coimbatore, 641 046, India.
authors.forename: Vijaya Padma
authors.initials: VP
authors.lastname: Vishwanadha
authors.affiliation: Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan.|Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D000071679:Glycogen Synthase Kinase 3 beta
keywords: ERα; GSK3β; metastasis; β-catenin