Extravillous trophoblast cell invasion is promoted by the CD44-hyaluronic acid interaction.
BACKGROUND
Extravillous trophoblast (EVT) cell invasion plays a crucial role in establishment of successful pregnancy. CD44, a cell-surface receptor for hyaluronic acid (HA), plays a key role in HA-mediated remodeling and degradation that triggers cancer cell invasion. However, few studies have reported on the expression or functions of CD44 in human EVT cells. We hypothesized that CD44-HA interaction was involved in invasion by EVT cells.


METHODS
To test our hypothesis, we conducted in situ examinations of CD44 and HA expression in the human first-trimester placenta. We also assessed the methylation status of CD44 promoter and exon 1 regions in EVT cells. Finally, we conducted transwell cell invasion assays using EVT cell lines and EVT cells isolated from first-trimester human villous explant cultures.


CONCLUSIONS
EVT cells, but not villous trophoblast cells, in the first-trimester placenta expressed CD44. HA was strongly expressed in adventitia surrounding the spiral uterine arterial walls of the decidua. The extent of demethylation of CD44 promoter and exon 1 CpG islands was increased in EVT cells compared to those of first-trimester chorionic villi (including villous trophoblast cells), suggesting that CD44 expression was, at least in part, associated with methylation status. Data from transwell cell invasion assay with siRNA knockdown of CD44 revealed that CD44 expression significantly promoted invasion by EVT cells in an HA-dependent manner.


CONCLUSIONS
The discovery of a CD44-HA interaction between EVT cells and the extracellular matrix contributes to our understanding of the mechanism underlying invasion by EVT cells.
Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan; Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan.
H
H
Takahashi
Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan.
T
T
Takizawa
Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan.
S
S
Matsubara
Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan.
A
A
Ohkuchi
Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan.
T
T
Kuwata
Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan.
R
R
Usui
Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
H
H
Matsumoto
Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Y
Y
Sato
Department of Obstetrics and Gynecology, Graduate School of Medicine Science, Kanazawa University, Ishikawa 920-8641, Japan.
H
H
Fujiwara
Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo 105-0003, Japan.
A
A
Okamoto
Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi 329-0498, Japan.
M
M
Suzuki
Department of Molecular Medicine and Anatomy, Nippon Medical School, 1-1-5 Sendagi, Tokyo 113-8602, Japan. Electronic address: t-takizawa@nms.ac.jp.
T
T
Takizawa
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D018899:CpG Islands / Q000235:genetics; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000096:biosynthesis / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D014327:Trophoblasts / Q000378:metabolism* / Q000502:physiology
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
CD44; Cell invasion; DNA methylation; Extravillous trophoblast cells; Human placenta; Hyaluronic acid