The pattern of expression of Notch protein members in normal and pathological endometrium

Abstract

The objective of this study was to investigate the pattern of expression and the localization of Notch-1, Notch-4 and Jagged-1 in physiological and pathological human endometrium and to evaluate the expression levels of two major regulators of the G1 checkpoint, namely cyclin D1 and p21. Sixty samples of physiological endometrium and 60 samples of pathological endometrium were used for the study. Evaluation of the expression level and the distribution of Notch pathway members and cell-cycle proteins was performed by immunohistochemistry. In the physiological endometrium we observed an increase of Notch-1 and Jagged-1 from proliferative to secretory phase and an opposite trend for Notch-4. In menopause, the level of expression of all three members of the Notch pathway decreased. We also observed a cyclin D1 increase from proliferative to secretory phase. By contrast, p21 showed a slight increase from proliferative to secretory phase. In the pathological endometrium, we observed an increase of Notch-1 expression from polyps to carcinoma and decrease for Notch-4 and Jagged-1. Moreover, we observed a higher expression of cyclin D1 in all the endometrial pathologies. By contrast, the expression level of p21 slightly increased from polyps to carcinoma. We concluded that in human endometrium Notch-4 seems to be more involved in controlling proliferation, whereas Notch-1 seems to be more involved in differentiation programming. Deregulation of these functions may induce the onset of several endometrial pathologies from polyps to cancer.

Notch-4 contributes to the metastasis of salivary adenoid cystic carcinoma

“…In oral squamous cell carcinoma, Notch-4 deregulation is implied to be related to the deregulation of developmental and differentiation pathways, as well as cell fate misspecification (17). Notch-4 also seems to be involved in the proliferation of human endometrium (18). The changes of Notch-4 expression level may induce the expression of two pro-angiogenic genes, NF-κB and MMP2, in cerebral endothelial cells (19).…”

Fetal–maternal communication: the role of Notch signalling in embryo implantation

“…Cobellis et al (2008) identified changes in the expression of Notch1, which was strongest during the mid-secretory phase, and Notch4, which was stronger during the proliferative phase. Conversely, Mitsuhashi et al (2012) more recently identified no differences in Notch1 and 3 across the cycle.…”

“…Notch1 and 3 protein primarily localize to the glandular epithelium (Cobellis et al 2008, Mitsuhashi et al 2012, whereas Notch4 localizes primarily to the stroma (Cobellis et al 2008). In the only study to examine transcript, Notch1 and 3 expressions are higher in endometrial stromal cells compared with epithelium (Mikhailik et al 2009); however, this analysis was performed following isolation and culture and therefore may not represent in vivo expression.…”

“…All four Notch receptors are present in the endometrium (Table 1 and Fig. 1A), Notch signalling during embryo implantation R77 although Notch2 has only been identified at the mRNA level (Cobellis et al 2008, Mikhailik et al 2009, Mitsuhashi et al 2012, Mori et al 2012.…”

NOTCH signalinio kelio ir ginekologinių piktybinių navikų sąsaja

“…Todėl manoma, kad NOTCH1 ir JAG1 gali būti svarbūs ląstelių diferenciacijai, o NOTCH4 -proliferacijai. Vėžinėse ląstelėse nustatytas NOTCH1 baltymo raiškos padidėjimas bei NOTCH4 ir JAG1 baltymų raiškos sumažė-jimas (30). Kitų autorių duomenimis, NOTCH1, NOTCH3, DLL4 ir JAG1 baltymų kiekiai yra vienodi tiek sekretuojančiame, tiek proliferuojančiame sveikame endometriume, todėl jie nėra svarbūs ląstelių proliferacijai ir diferenciacijai.…”