Expression of Gadd45α in human early placenta and its role in trophoblast invasion

Placenta. 2014 Jun;35(6):370-7. doi: 10.1016/j.placenta.2014.03.020. Epub 2014 Apr 12.

Abstract

Objectives: 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.

Discussion and conclusion: 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.

Keywords: Gadd45α; MMPs; Trophoblast invasion; Trophoblast migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Cycle Proteins / analysis
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / physiology*
  • Cell Line
  • Cell Movement
  • Cell Proliferation
  • Chorionic Villi / metabolism
  • Decidua / metabolism
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Nuclear Proteins / analysis
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology*
  • Placenta / metabolism*
  • Placenta / physiology*
  • Placentation / physiology
  • Pregnancy
  • Pregnancy Trimester, First
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Tissue Culture Techniques
  • Tissue Inhibitor of Metalloproteinase-1 / analysis
  • Tissue Inhibitor of Metalloproteinase-2 / analysis
  • Trophoblasts / physiology*

Substances

  • Cell Cycle Proteins
  • GADD45A protein, human
  • Nuclear Proteins
  • RNA, Small Interfering
  • TIMP1 protein, human
  • TIMP2 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9