Promyelocytic leukaemia (PML) protein expression in human placenta and choriocarcinoma

Abstract

Promyelocytic leukaemia (PML) protein, the product of the pml gene, is heterogeneously expressed in various normal and neoplastic tissues, and the fusion of the pml gene with retinoic acid receptor-alpha is believed to be a central mechanism in acute PML tumourigenesis. As PML is important for controlling major cellular processes, such as growth and differentiation, it is believed that it plays an important role during human gestation. The human placenta is a critical organ for the maintenance of gestation, but the expression pattern and functional significance of PML in the placenta have not been documented. The present study has therefore investigated the expression of PML in the human placenta and in choriocarcinoma, and has observed the biological effects following the overexpression of PML in choriocarcinoma cell lines (BeWo and JEG-3). In the human placenta, PML expression was readily found in villous stromal fibroblasts, capillary endothelial cells, Hofbauer cells, and occasionally in amnion cells. Moreover, immunoblotting of placental lysates demonstrated increased PML expression with increasing gestation. Interestingly, PML expression was confined to intermediate trophoblasts and syncytiotrophoblastic giant cells at the placental site (placental site giant cells) in the trophoblastic cell population. Intermediate trophoblasts at non-placental sites, and villous cytotrophoblasts and syncytiotrophoblasts consistently did not express PML. Further screening of PML expression in hydatidiform moles (n = 4) and choriocarcinomas (n = 7) also revealed selective PML expression in intermediate trophoblastic cells and syncytiotrophoblastic cells, but not in the cytotrophoblastic populations, which corresponds well with observations in the placental bed. Adenoviral transduction of PML resulted in a marked reduction in cell growth in both choriocarcinoma cell lines, which was associated with increased apoptosis. The findings of the present study strongly suggest that PML plays an important role in human placental development and growth, and in the pathobiology of trophoblasts and trophoblastic neoplasia.

Dysregulation of Promyelocytic Leukemia (PML) Protein Expression in Preeclamptic Placentae

“…Our study is consistent with previous reports 22 in that PML expression is detectable in normal placenta localizing within diffuse or speckled nuclear bodies throughout gestation. This heterogeneous morphology is limited to specific cell-types of the villus stroma, including capillary endothelial cells, villus stromal fibroblasts, and resident macrophages but not villus cytotrophoblast or syncytiotrophoblast 22.…”

“…In summary, our findings agree with previous studies showing PML expression within cells of the villus core, but not trophoblast, in normal placentae 22. We extended these studies to show that nuclear PML expression is elevated within these cells, but not trophoblast, in preeclamptic placentae.…”

“…Temporally, PML protein expression in normal placentae has been reported to increase as gestation proceeds to term 22. Our study extends these observations by including preeclamptic samples.…”

“…Additionally, it may reduce hypoxia-induced angiogenesis through inhibition of hypoxia-inducible factor 1-alpha (HIF-1α) protein synthesis 18. In correlative support of this, increased expression of HIF-1α protein is most notable in syncytiotrophoblast of preeclamptic placentae 42, where there is relatively little PML expression (current study and 22). Thus, ischemic stress may enable increased HIF-1α production but PML-mediated inhibition of HIF-1α protein translation may result in heterogenous expression of HIF-1α protein between different cell types.…”

“…Expression of PML within villi of normal placentae was described by Kim et al 22 to be most notable in fibroblasts, endothelial cells of fetal stem vessels and macrophages. Temporally, expression of nuclear PML tends to increase with gestational age and remains high from approximately 31 weeks gestation to term and suggests that PML contributes to regulating growth and development of the placenta 22.…”