Changes in Vasodilator-Stimulated Phosphoprotein Phosphorylation, Profilin-1, and Cofilin-1 in Accreta and Protection by DHA

Abstract

Accreta and gestational trophoblastic disease (ie, choriocarcinoma) are placental pathologies characterized by hyperproliferative and invasive trophoblasts. Cellular proliferation, migration, and invasion are heavily controlled by actin-binding protein (ABP)-mediated actin dynamics. The ABP vasodilator-stimulated phosphoprotein (VASP) carries key regulatory role. Profilin-1, cofilin-1, and VASP phosphorylated at Ser157 (pVASP-S157) and Ser239 (pVASP-S239) are ABPs that regulate actin polymerization and stabilization and facilitate cell metastases. Docosahexaenoic acid (DHA) inhibits cancer cell migration and proliferation. We hypothesized that analogous to malignant cells, ABPs regulate these processes in extravillous trophoblasts (EVTs), which exhibit aberrant expression in placenta accreta. Placental-myometrial junction biopsies of histologically confirmed placenta accreta had significantly increased immunostaining levels of cofilin-1, VASP, pVASP-S239, and F-actin. Treatment of choriocarcinoma-derived trophoblast (BeWo) cells with DHA (30 µM) for 24 hours significantly suppressed proliferation, migration, and pVASP-S239 levels and altered protein profiles consistent with increased apoptosis. We concluded that in accreta changes in the ABP expression profile were a response to restore homeostasis by counteracting the hyperproliferative and invasive phenotype of the EVT. The observed association between VASP phosphorylation, apoptosis, and trophoblast proliferation and migration suggest that DHA may offer a therapeutic solution for conditions where EVT is hyperinvasive.

Biomolecules Involved in Both Metastasis and Placenta Accreta Spectrum—Does the Common Pathophysiological Pathway Exist?

“…In a study performed by Ali et al, it was observed that placenta accreta, a medical condition characterized by abnormal attachment of the placenta to the uterine wall, expresses higher levels of CFL-1 in comparison to normal placentation. Moreover, they observed that only CFL-1 had significantly increased levels in focal accreta [127].…”

“…CFL-1 belongs to the actin depolymerizing factor/cofilin family and is the most abundant and ubiquitous member of the family in all studied non-muscle cells and in embryonic muscle cells [124,125]. CFL-1 is crucial for cell survival, as its primary function is to bind and depolymerize filamentous F-actin and prevent the polymerization of monomeric G-actin into filamentous F-actin, resulting in dynamic rearrangement of the actin cytoskeleton [125][126][127].…”

“…The actin cytoskeleton plays a major role in the formation of many essential cellular structures such as microvilli and cellular junctions, which transform early pregnancy in mammals. CFL-1 plays an important role in decidualization (the process of preparing the uterus for implantation) and blastocyst implantation [125,127,130]. In a study performed by Ali et al, it was observed that placenta accreta, a medical condition characterized by abnormal attachment of the placenta to the uterine wall, expresses higher levels of CFL-1 in comparison to normal placentation.…”

“…Additionally, CFL-1 expression is increased in the invasive subpopulation of tumor cells in mammary tumors [135,136]. Furthermore, it has been noted that the activity status of CFL-1 is related to invasion and metastasis [127,132,134,137].…”

The effect of obesity on uterine receptivity is mediated by endometrial extracellular vesicles that control human endometrial stromal cell decidualization and trophoblast invasion

“…We demonstrated that basal cell adhesion molecule (BCAM, involved in trophoblast proliferation, migration, and invasion; Liu et al, 2022) was significantly less abundant in endometrial EVs from obese women than in endometrial EVs from nonobese women (by a factor of 1.6 in the XIC analysis). Conversely, we found that cofilin-1 (COF1, which is involved in actin remodelling and dynamics; Ali et al, 2019) is significantly more abundant in endometrial EVs from obese women than in endometrial EVs from nonobese women (by a factor of 0.6 in the SC analysis). Since these seven proteins are differentially expressed in endometrial EVs from obese vs. nonobese women, they might be potential biomarkers of endometrial receptivity.…”