Abstract
The regulation mechanisms involved in matrix metalloproteinase (MMP) expression and the motility of human endometrial and decidual stromal cells (ESCs and DSCs, respectively) during decidualization remain unclear. DSCs show significant increased cell motility and expression of FOS-like 1 (FOSL1) and MMP1, MMP2, and MMP9 compared with ESCs, whereas lack of decidualization inducers leads to a rapid decrease in FOSL1 and MMP1 and MMP9 expression in DSCs in vitro Therefore, we hypothesized that a link exists between decidualization inducers and FOSL1 in up-regulation of motility during decidualization. Based on the response of ESCs/DSCs to different decidualization systems in vitro, we found that progesterone (P4) alone had no significant effect and that 17β-estradiol (E2) significantly increased cell motility and FOSL1 and MMP1 and MMP9 expression at the mRNA and protein levels, whereas 8-bromo-cAMP significantly decreased cell motility and FOSL1 and MMP9 expression in the presence of P4. In addition, we showed that E2 triggered phosphorylation of estrogen receptor 1 (ESR1), which could directly bind to the promoter of FOSL1 in ESCs/DSCs. Additionally, we also revealed silencing of ESR1 expression by siRNA abrogated E2-induced FOSL1 expression at the transcript and protein levels. Moreover, silencing of FOSL1 expression by siRNA was able to block E2-induced MMP1 and MMP9 expression and cell motility in ESCs/DSCs. Taken together, our data suggest that, in addition to its enhancement of secretory function, the change in MMP expression and cell motility is another component of the decidualization of ESCs/DSCs, including estrogen-dependent MMP1 and MMP9 expression mediated by E2-ESR1-FOSL1 signaling.
Highlights
The regulation mechanisms involved in matrix metalloproteinase (MMP) expression and the motility of human endometrial and decidual stromal cells (ESCs and DSCs, respectively) during decidualization remain unclear
We found significant up-regulation in MMP1, MMP2, and MMP9 expression, migration, and invasion of human DSCs compared with endometrial stromal cell (ESC)
By observing the MMP expression profile of DSCs during 96-h culture without a decidualization inducer after isolation from the decidua, we found a rapid decline in MMP1 and MMP9 expression, which may indicate dependence of MMP1
Summary
Primary ESCs isolated from the secretory endometrium and DSCs isolated from early-pregnancy decidua were identified as stromal cells based on their fusiform appearance, observed under an optical microscope, and their cell-specific expression, determined via immunofluorescence (IF) staining: vimentin-positive (mesenchyme origin–specific, green) and cytokeratin 7–negative (epithelial cell–specific, red) (Fig. 1A). The results from qRT-PCR (Fig. 3, H and M) and WB and their quantitative representation (Fig. 3, I, J, N, and O) revealed that the expression of FOSL1 and MMP9 in ESCs/DSCs showed a consistent change with cell migration and invasion; their expression was increased by E2 ϩ P4, decreased by 8-Br-cAMP ϩ P4, and not affected by P4 compared with vehicle at both the mRNA and protein levels. Similar to ESCs, FOSL1 siRNA-1 and -2 transfection significantly decreased the length of wound closure and the number of invaded cells (Fig. 5, E and F) as well as mRNA (Fig. 5H) and protein (Fig. 5, I, bottom row, J, M, and N) expression of FOSL1 and MMP1 and MMP9, whereas NC siRNA pretreatment did not cause significant changes in DSCs. mRNA and Figure 5. These results suggested that E2-induced MMP1 and MMP9 expression, migration, and invasion during decidualization depended on FOSL1
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