NME1 at the human maternal–fetal interface downregulates titin expression and invasiveness of trophoblast cells via MAPK pathway in early pregnancy

Abstract

Nometastatic gene 23-H1 (NME1, also known as nm23-H1) is a wide-spectrum tumor metastasis suppressor gene that plays an important role in suppressing the invasion and metastasis of tumor cells. It has been demonstrated that NME1 is also expressed in human firsttrimester placenta, but its function at maternal-fetal interface is not clear. The present study aimed to elucidate the biological function of NME1 at the maternal-fetal interface, especially on invasion of the human extravillous cytotrophoblasts (EVCTs). NME1 has been identified in both human trophoblast cells and decidual stromal cells (DSCs) in early pregnancy. We have proved that NME1 silencing in vitro increases the titin protein translation in the invasive EVCTs. Moreover, NME1 can inactivate the phospho-extracellular signalregulated kinase 1/2 (P-ERK1/2) in trophoblasts in a time-dependent manner, and U0126, an inhibitor of MAPK/ERK, can inhibit partly the enhanced invasiveness and titin expression in trophoblasts induced by NME1 silencing. Interestingly, the expression of NME1 in either villi or decidua is higher significantly in miscarriage than that of the normal early pregnancy. These findings first reveal that the NME1 expressed in trophoblasts and DSCs controls the inappropriate invasion of human first-trimester trophoblast cells via MAPK/ERK1/2 signal pathway, and the overexpression of NME1 at maternal-fetal interface leads to pregnancy wastage.

Potential ligand-receptor-pathway cascades and a novel non-metabolic function of lactate in remodeling uterine receptivity by inducing endometrial histone lactylation at implantation, revealed by a proteomic atlas of maternal-fetal crosstalk

“…Our reanalysis showed that the level of NME1 was signi cantly lower in endometrium of endometriosis (Fig. S2E), which is in line with the previous notion that NME1 plays an important role in regulating the invasiveness of trophoblast cells and participates in the pathogenesis of endometriosis (81,82). Similarly, the level of FKBP1A is also signi cantly lower in endometrium of endometriosis (Fig.…”

“…Based on the well-established database of membrane and secreted proteins, we predicted a variety of ligand-receptor complexes at the protein level that might be essential for conceptus-endometrium crosstalk. The predictability of our constructed interaction map was supported by a series of membrane or secreted partners that have been identi ed as key regulators of successful implantation or uterine pathology, such as calpain 2 (CAPN2) (79), integrin subunit alpha 9 (ITGA9) (47,80), and non-metastatic gene 23-H1 (NME1) (81,82). For example, membrane protein CAPN2 is highly expressed in endometrial tissues, while its interacting secreted protein cathepsin B (CTSB) is enriched in the conceptus (Fig.…”

Tissue transglutaminase-2 promotes gastric cancer progression via the ERK1/2 pathway

“…The ERK1/2 signaling pathway has been reported to be involved in cell growth [ 16 ] and migration [ 23 ]. Thus, we measured TG2 and assessed whether it could modulate activation of the ERK1/2 signaling pathway in GC cells.…”

Missing and overexpressing proteins in domestic cat oocytes following vitrification and in vitro maturation as revealed by proteomic analysis

“…Titin is a calcium-responsive protein, which is a group that is responsible for oocyte meiosis resumption [ 44 ]. Expression of titin in the human trophoblast is involved in the processes of placentation and embryo development [ 45 ]. Contactins, a subgroup of molecules belonging to the immunoglobulin superfamily, consists of six members: contactin, TAG-1, BIG-1, BIG-2, NB-2 and NB-3.…”