MEG3

Maternally Expressed 3 (MEG3) is an imprinted lncRNA which is expressed in many di fferent cell types and tissues and acts as a tumor suppressor and is downregulated in many types of cancer. Physiologically, MEG3 acts by stabilising p53 and activating apoptotic responses [244]. Zhang and coworkers [34] analysed MEG3 RNA levels in 30 placentas from preeclamptic women, compared to 30 control samples and found a statistically significant 80% downregulation. These results were consistent with those of Yu and coworkers [245] studying a cohort of 20 preeclamptic and 20 control placentas, finding that MEG3 RNA was only 28% of the RNA levels of the control group. To elucidate in more detail the function of MEG3 in placenta, Zhang and coworkers (2015) overexpressed MEG3 in two trophoblast cell lines (JEG3 and HTR-8/SVneo), showing enhanced antiapoptotic e ffects, while downregulation of MEG3 increased the apoptotic cells. Analysis of protein markers showed how MEG3 downregulation increased the levels of pro-apoptotic proteins such as Caspase-3 and Bax. These results contrast with what is observed in cancer, where MEG3 expression is rather associated with the activation of proapototic pathways, possibly suggesting a di fferent mode of action of MEG3 in these cell types. Yu and coworkers [245] focused on the link between MEG3 expression and endothelial-mesenchymal transition (EMT). During implantation and placentation, the trophoblasts undergo EMT in order to be able to migrate and invade the maternal tissues. MEG3 downregulation correlated with increased E-cadherin levels and downregulation of mesenchymal markers such as N-cadherin, vimentin, slug (encoded by the gene SNAI2), in placental RNA and protein extracts, placental sections and in vitro tests (HTR-8/SVneo trophoblast cell line). Changes in MEG3 expression did not influence proliferation but MEG3 overexpression promoted migration and trophoblasts invasion through matrigel matrixes [34,224]. Altogether, MEG3 protects from apoptosis, promotes migration and invasion by regulating endothelial-mesenchymal transition in trophoblast cells and therefore its downregulation possibly a ffects trophoblast invasion and placentation, playing a key role in preeclampsia. Consistently, the imprinting control region (IG-DMR) of the DLK1-MEG3 cluster was very recently found hypermethylated in human umbilical veins from preeclamptic pregnancies, with an altered expression of both imprinted genes, a lower secretion of nitrite, VEGF and a higher secretion of endothelin 1 (ET1) all factors able to mediate pathological mechanisms in the o ffspring from preeclampsias [246].
