Effect Of Decidua And Its Factors On Trophoblast Invasion And The Role Of MAPK In The Regulation

OBJECTIVE:Successful human placentation requires that trophoblast rapidly invade the uterus and tap into the maternal circalution. In contrast to tumor cell ivasion,trophoblast invasion is precisely regulated,being confined spatially to uterus and temporally to early pregnancy. The uterine microenvironment (particular decidua) plays an important role in the control of trophoblast invasion. The invasiveness of trophoblast derived from first trimester pregnancy can be inhibited by decidual cell conditioned media (DCM),while the mechanism is not very clear. In this research,we firstly investigated the effect of DCM on the expression of genes that were involved in regulation of first trimester trophoblast invasion. Secondly,the molecular mechanisms of MMP-9 induction in trophoblast cells by different factors were tested. Thirdly,we studied the role of MAPK on the regulation of JAR cells invasion. METHOD:Cellular ELISA was used to detect the kinase activity stimulated by IL-lp,TNF-a and PMA. RT-PCR was applied to study the expression of genes. Transwell invasion system was employed to observe the invasion of JAR cells. MTT was used to show the proliferation,activity of JAR cells cultured in vitro. RESULTS:1. Trophoblast derived from first trimester pregnancy expressed MMP-2,MMP-9,TIMP-1 and uPA,but not TIMP-2,PA I-1.The first trimester and term DCM down-regulated the expression level of MMP-2,MMP-9,uPA and up-regulated theexpression level of TIMP-1,PAI-1.2. In trophoblast,ERK and p38 were activated on the stimulation of IL-lp,TNF-a and PMA. MMP-9 mRNA induction by the stimulators could be inhibited significantly by specific inhibitor for ERK and p38.3. In JAR cells,MMP-2,MMP-9 and uPA mRNA induced with PMA could be inhibited significantly by specific inhibitor for ERK or p38.4. MAPK was activated dose-dependly on the stimulation of PMA. SB203580,a inhibitor of p38 MAPK,reduced PMA-induced JAR cells invasion in vitro. CONCLUTION:1. DCM could exhibit its anti-invasive activity to regulate the expression of genes such as MMP-2,MMP-9,TIMP-1,uPA and PAI-1 in trophoblast.2. Decidual cells might excrete some factors activating or blocking MAPK signal transduction to regulate the expression of some genes involved in invasion.3. MAPK could play important roles in the regulation of MMP-2,MMP-9,TIMP-2,uPA gene expression in trophoblast. Activation of p38 might contribute to a more invasive phenotype of JAR cells. Targeting of p38 using SB 203580 may provide a novel means of controlling choriocarcinoma.