title: Functional antagonism between high temperature requirement protein A (HtrA) family members regulates trophoblast invasion.
abstract: Human trophoblast invasion of decidualized endometrium is essential for placentation and is tightly regulated and involves trophoblast-decidual cell interaction. High temperature requirement A4 (HtrA4) is a secreted serine protease highly expressed in the invasive extravillous trophoblasts that invade decidua. In contrast, both HtrA1 and HtrA3 have been shown to inhibit trophoblast invasion. Here we provide evidence that decidua-secreted HtrA1 and HtrA3 antagonize HtrA4-mediated trophoblast invasion. We demonstrated that HtrA1 and HtrA3 interact with and degrade HtrA4 and thereby inhibit trophoblast-like JAR cell invasion. Specifically, HtrA1 and HtrA3 expression is up-regulated under decidualization conditions in endometrial stromal and epithelial cells, T-HESCs and Ishikawa cells, respectively. Conditioned media from these two cell lines after decidualization treatment suppress HtrA4-expressing JAR cell invasion in an HtrA1- or HtrA3-dependent manner. Co-culture of the HtrA4-expressing JAR cells with decidualization stimuli-treated T-HESC or Ishikawa monolayer also impairs JAR cell invasion, which can be reversed by HtrA1 or HtrA3 knockdown, supporting that HtrA1 and HtrA3 are crucial for trophoblast-decidual cell interaction in the control of trophoblast invasion. Our study reveals a novel regulatory mechanism of trophoblast invasion through physical and functional interaction between HtrA family members.
authors.affiliation: Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Yao-Yu
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Pei-Yun
authors.initials: PY
authors.lastname: Chuang
authors.affiliation: Division of High Risk Pregnancy, Mackay Memorial Hospital, Taipei 104, Taiwan.
authors.forename: Chie-Pein
authors.initials: CP
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Yueh-Ho
authors.initials: YH
authors.lastname: Chiu
authors.affiliation: Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Hsiao-Fan
authors.initials: HF
authors.lastname: Lo
authors.affiliation: Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei 106, Taiwan.
authors.forename: Mei-Leng
authors.initials: ML
authors.lastname: Cheong
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan 704, Taiwan, and.
authors.forename: Jyun-Yuang
authors.initials: JY
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan 704, Taiwan, and.
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan,; Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan. Electronic address: hwchen@gate.sinica.edu.tw.
authors.forename: Hungwen
authors.initials: H
authors.lastname: Chen
mesh_terms: D005260:Female; D057809:HEK293 Cells; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D012697:Serine Endopeptidases / Q000378:metabolism*; D057057:Serine Proteases / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology*
chemical_list: C576189:HtrA4 protein, human; D057057:Serine Proteases; C474013:HTRA3 protein, human; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases
keywords: Cell Invasion; Gene Expression; Placenta; Pregnancy; Protease; Trophoblast