Successful pregnancy depends on the ability of trophoblast cells to invade the uterine decidual stroma and to gain access to the maternal circulation, which is a mechanism similar to that of tumor cells. However, as opposed to malignant invasion, the trophoblast invasion is strictly limited in normal pregnancy. These events are regulated by the cross-talking of paracrine and autocrine factors between the trophoblast cells and DSCs at the maternal-fetal interface. DSCs secrete a lot of cytokines and express proteins, such as TIMP1, that control the invasiveness of the trophoblast cells. As a wide-spectrum tumor metastasis suppressor gene, CD82 is expressed in the primary DSCs but not in the primary trophoblast cells, so CD82 might be the media of cross-talking between DSCs and trophoblast cells. Consistent with transcription level, the decidua from the unexplained miscarriage had a much higher CD82 protein expression than that of the normal early pregnancy termination, based on immunohistochemistry and Western blot (P < 0.01; Fig. 8, b and c), which suggests that the CD82 overexpression in decidua restricted the appropriate invasion of trophoblasts, leading to early pregnancy wastage. Therefore, in the present study, we have investigated whether the DSCs-expressed CD82 regulates the invasion of trophoblast cells. As shown in Figure 3 and Figure 5, we have demonstrated that human DSCs from the first-trimester pregnancy express CD82 that inhibits the invasion of trophoblast cells through up-regulating the transcription and translation of TIMP1. DSCs and trophoblast cells produce TIMP1, which controls MMP secretion of DSCs and trophoblast cells. MMPs are partly responsible for placentation and spiral artery remodeling. MMPs are involved in pregnancy complications, including not only spontaneous abortion but also preeclampsia, fetal growth restriction, and so on, that result from an insufficient invasion of trophoblasts.
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Our observations show that CD82 deactivates MAPK3/1 and down-regulates the expression of integrinp1, and anti-integrinp1 neutralizing antibody reinforces the deactivation of MAPK3/1 and the increase in expression of TIMP1 induced by CD82, which suggests that CD82 stimulates the expression of TIMP1 via the integrinp1/MAPK/MAPK3/1 signaling pathway as well as other signal pathways involved in the invasion of trophoblast cells. The mechanism of CD82-mediated tumor metastasis suppression is not fully understood, but a series of the CD82-associated molecules, such as EGFR, integrinp1, and E-cadherin are involved.
FIG. 8. The transcription and protein translation of CD82 increase significantly in the decidua of the unexplained miscarriage. CD82 transcription and translation in human decidua was analyzed by quantitative real-time PCR (a), immunohistochemistry (b), or Western blot (c). The relative fold expression of the CD82 in decidua is compared between the miscarriage and normal early pregnancy. These pictures are representatives of six individual experiments. Error bars depict the standard error of the mean. Pregnancy, the decidua from normal early pregnancy;miscarriage, the decidua from the unexplained miscarriage. **P < 0.01, compared to pregnancy. Original magnification (b) X200.