title: Expression of Gadd45α in human early placenta and its role in trophoblast invasion.
abstract: OBJECTIVE
  Well-controlled trophoblast migration and invasion at the maternal-foetal interface are crucial events for normal placentation and successful pregnancy. Growing evidence has revealed that growth arrest and DNA damage-inducible 45 alpha (Gadd45α) participates in tumour migration and invasion as a tumour suppressor. However, the expression and function of Gadd45α in trophoblasts is unknown. This study aimed to determine the Gadd45α expression and function in the human first trimester placenta and identify the underlying mechanisms.
  
  
  METHODS
  The expression of Gadd45α in human first trimester placenta was determined using immunohistochemistry. HTR8/SVneo cell line was used to investigate the effects of Gadd45α on proliferation, apoptosis, migration/invasion, matrix metalloproteinase (MMP)2/9 activities, and tissue inhibitor of metalloproteinase (TIMP)1/2 expression using cell proliferation assays, flow cytometric analysis, transwell migration/invasion assays, gelatin gel zymography, and western blotting, respectively. Moreover, a placental villous explant model was employed to verify its functions in placentation.
  
  
  RESULTS
  Gadd45α was strongly expressed in syncytiotrophoblasts and trophoblast columns of human placental villi, extravillous trophoblast cells and glandular epithelium within the maternal decidua. Gadd45α knockdown significantly promoted migration and invasion of HTR8/SVneo cells, whereas it did not affect cell proliferation or apoptosis. Silencing Gadd45α also enhanced trophoblast outgrowth and migration in placental explants. These effects were related to increased activities of MMP2/9 and the decreased expression of TIMP1/2.
  
  
  CONCLUSIONS
  Gadd45α may be involved in human trophoblast migration and invasion and may function as an important negative regulator at the foetal-maternal interface during early pregnancy by directly or indirectly regulating MMP2/9 activities.
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Chongqing Health Center For Women and Children, No. 64 Jintang Street, Yuzhong District, Chongqing 400013, China.
authors.forename: H
authors.initials: H
authors.lastname: Mu
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.affiliation: Laboratory of Lipid and Glucose Research, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
authors.forename: X
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
authors.forename: N
authors.initials: N
authors.lastname: Yin
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China. Electronic address: qihongbocy@gmail.com.
authors.forename: H
authors.initials: H
authors.lastname: Qi
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002824:Chorionic Villi / Q000378:metabolism; D003656:Decidua / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D010920:Placenta / Q000378:metabolism* / Q000502:physiology*; D010929:Placentation / Q000502:physiology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D046509:Tissue Culture Techniques; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D014327:Trophoblasts / Q000502:physiology*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human
keywords: Gadd45α; MMPs; Trophoblast invasion; Trophoblast migration