Green Tea Catechins Regulate the Growth and Chorionic Gonadotropin Production in Placental Trophoblasts

Trophoblasts are specialized cells of the placenta that form the outer layer of a blastocyst and comprise mononuclear cytotrophoblasts and multinucleated syncytiotrophoblasts. They help the fertilized egg implant into the uterine wall during pregancy through producing chorionic villi and human chorionic gonadotropin (hCG), which can stimulate progesterone secretion to sustain a pregnancy. The cytotrophoblast can increase in number and fuse together to form the syncytiotrophoblast due to mitogenesis and differentiation. But in placental choriocarcinoma, a type of gestational trophoblastic disease (GTD), trophoblasts develop into tumor cells due to their starting to proliferate uncontrollably and later spread quickly. The choriocarcinoma is characterized by no formation of chorionic villi but by elevated blood levels of hCQ as well as may be preceded by spontaneous abortion in 20% of cases or hydatidiform mole in 50%, and having symptoms of vaginal bleeding, shortness of breath, enlarged uterus, chest pain, and hyperemesis. Despite the facts that trophoblasts are important during pregnancy and in GTD, trophoblastic cell growth, hCG production and other functions are regulated by oxidative stress, nutrients and vitamins.Green tea catechins (GTC) are also called vitamin P, and they have the prooxidant or antioxidant activity, depending on the dosage and cell type. Epigallocatechin gallate (EGCG) is the most abundant in unfermented tea. GTC can circulate to the placenta in animals and in the blood of humans after consumption. Pregnant rats given GTC had the highest levels of EGCG in the placenta and the fetus, and pregnant mice injected with GTC were protected against transplacental carcinogenesis. No studies have demonstrated whether any of GTC affects trophoblast growth and hCG production. To fully understand the impacts of GTC, especially EGCG, on the placenta, trophoblasts and trophoblast-associated disease, our initial goals are to use normal human villous trophoblasts (HVT) and human placental choriocarcinoma cells (HPCC) in order to investigate the pathway involved in GTC modulations of trophoblast growth and hCG production. Aims I and II are to study the pathway involved in the growth regulation and hCG production in HVT by GTC, respectively. Aims III and IV are to study the pathway involved in the growth regulation and hCG production of HPCC by GTC, respectively. Aim V is to study the in vivo effect of GTC on placental trophoblast and CG production in normal mice. Aim VI is to study the in vivo effects of GTC on trophoblastic tumor growth and hCG production in HPCC-xenografted mice. Our preliminary data showed that EGCG but not other GTC, reduced cell number and hCG protein levels in HVT and HPCC, such as BeWo, JEG-3 and JAR. We found that EGCG stimulated AMPK activity, as well as the phosphorylation of ERK1/2, p38, but not JNK, proteins. EGCG reduced AKT phosphorylation in HVT but not in HPCC.We anticipate being the first lab to elucidate a signaling mechanism that underlies novel actions of GTC on growths and hCG production in HVT and HPCC. This project also leads us to a better understanding of how consumption of high-EGCG tea acts on the placenta in pregnant animal. As tea production and tea drink are very important in Taiwan, our new discoveries from novel actions of GTC on trophoblasts may provide the fundamental basis for improving and creating the high value added tea product. Understanding what signaling elements transduce distinct EGCG signals between normal and cancerous trophoblasts may provide the intellectual merits for academic development plan that evaluates a clinical trial of the effect of EGCG-related drugs in GTD. We gain new further insights into GTC’s role in the reproduction, health food and biomedical disease.