Activation of G protein-coupled estrogen receptor stimulates placental human chorionic gonadotropin expression through PKA-CREB signaling.

The placenta-secreted human chorionic gonadotropin (hCG) is a hormone that plays a critical role in inducing ovarian progesterone production, which is required for maintaining normal pregnancy. The bioavailability of hCG depends on the expression of the beta-subunit of hCG (hCG-ß) which is encoded by the chorionic gonadotropin beta (CGB) gene. G protein-coupled estrogen receptor (GPER) is a membrane estrogen receptor involved in non-genomic estrogen signaling. Estradiol (E2) has been shown to stimulate hCG production. However, the role of the GPER in regulating CGB expression remains unknown. In the present study, our results revealed that treatment with G1 upregulated CGB expression in two human choriocarcinoma cell lines, BeWo and JEG-3, and primary human cytotrophoblast cells. In addition, G1 treatment activated the cAMP-response element binding protein (CREB). Using a pharmacological inhibitor and siRNA-mediated knockdown approach, we showed that the stimulatory effect of G1 on CGB expression is mediated by the protein kinase A (PKA)-CREB signaling pathway. This study increases the understanding of the role of GPER in the human placenta. In addition, our results provide important insights into the molecular mechanisms that mediate hCG expression, which may lead to the development of alternative therapeutic approaches for treating placental diseases.

Lapatinib Inhibits Amphiregulin-induced BeWo Choriocarcinoma Cell Proliferation by Reducing ERK1/2 and AKT Signaling Pathways.

BACKGROUND: Human choriocarcinoma is the most aggressive type of gestational trophoblastic neoplasia. The expression of epidermal growth factor receptor (EGFR) in choriocarcinomas is significantly higher than those of trophoblastic cells in healthy placentas. Lapatinib is a potent EGFR and human epidermal growth factor receptor 2 (HER2) inhibitor that inhibits cell proliferation and induces apoptosis in various human cancer cells. Amphiregulin (AREG) is the most abundant EGFR ligand in amniotic fluid during human pregnancy. AIM: To explore the role of AREG in human choriocarcinoma cell proliferation. MATERIALS AND METHODS: The effect of lapatinib and AREG on cell proliferation was examined by the MTT assay. Western blots were used to investigate EGFR and HER2 expression, and the activation of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathways. RESULTS: Treatment with lapatinib reduced BeWo cell proliferation by inducing apoptosis. Moreover, AREG treatment stimulated BeWo cell proliferation by activating ERK1/2 and PI3K/AKT signaling pathways, which was blocked by lapatinib. CONCLUSION: Targeting EGFR/HER2 might be a useful therapeutic strategy for human choriocarcinoma.

Role of hysterectomy in the management of patients with gestational trophoblastic neoplasia: importance of receiving treatment in reference centers.

OBJECTIVE: To evaluate hysterectomy prevalence, indications and impact on clinical outcomes in a reference center in southern Brazil. STUDY DESIGN: Institutional Ethical Committee approval was granted for this study. In a cohort study spanning 21 years, all patients who underwent hysterectomy for gestational trophoblastic neoplasia (GTN) were included, and technical differences between hysterectomy performed in the reference center and those performed elsewhere were evaluated as well. RESULTS: Of 1,023 patients with gestational trophoblastic disease, 57 (5.6%) underwent hysterectomy (95% CI, 4.3-7.1). Hysterectomy incidence in 230 GTN patients was 17.7% (95%CI, 15.1-23.3). Indications for 41 hysterectomies in the reference center were as follows: primary treatment in 14 (34.1%) cases and secondary treatment in 27 (65.9%); of these, the main indications were GTN recurrence (7 [25.9%] cases), hemorrhage (6 [22.2%]), resistance to single-agent chemotherapy in patients who refused more aggressive treatment (6 [22.2%]), and tumor mass reduction (5 [18.5%]). Twelve (92.3%) of the 13 hysterectomies with bilateral oophorectomy were performed elsewhere (p < 0.001). Thirty-five (85.4%) patients had no complications, and median hospitalization time was short (3 +/- 4 days). None of the 4 deaths were associated with hysterectomy. In the reference center, when associated with hysterectomy, GTN cure rates reached 93% after 63 +/- 87 months of follow-up. CONCLUSION: When treatment is in a reference center, hysterectomy frequency and morbidity may be low, and indications due to hemorrhage are significantly lower. Furthermore, at a reference center there is significantly greater ovarian preservation at the time of hysterectomy, and significantly more patients who undergo hysterectomy have low-risk GTN.