Functional analysis of p21Cip1/CDKN1A in trophoblastic cells of the placenta and its roles in preeclampsia

先兆子痫(PE)是妊娠期的一种严重疾病，是导致孕产妇和围产儿死亡和发病率的最常见原因，导致母子双方的长期并发症。PE与严重的胎盘细胞功能障碍有关，其特征是增殖、分化、融合、侵袭、凋亡、自噬和衰老。有趣的是，肿瘤进展和怀孕有许多共同特征。细胞周期抑制因子p21Cip1/CDKN1A(P21)通过调节不同的细胞过程，在分子肿瘤学中发挥关键作用。虽然胎盘的发育依赖于滋养层细胞增殖和分化的精确协调，但对p21这样的细胞周期调控因子知之甚少。事实上，已有研究表明p21的表达在胎盘发育过程中起重要作用，并在PE中发生改变。因此，人们很容易提出p21对于滋养层细胞的功能至关重要，它的调节失调可能在其发病机制中起作用。为了验证这一假说，我们将系统地研究p21在不同滋养层细胞系中的表达、定位以及在PE不同阶段的原代胎盘组织中的分子作用。尽管进行了深入的研究，但PE的发病机制尚不完全清楚，目前还没有可用的治疗方法。阐明PE的复杂性并进一步了解其改变的分子途径具有重要的临床意义。关于p21s在PE中作用的一般发现对滋养细胞生物学具有关键作用，并将有助于理解这种严重的不可预测和不可预防的疾病。此外，滋养层细胞为癌症和干细胞研究提供了一个极具吸引力的模型。

Preeclampsia (PE), a serious disease during pregnancy, is the most common cause of maternal and perinatal mortality and morbidity contributing to long-term complications in mother and offspring. PE is associated with profound placental cellular dysfunctions characterized by altered proliferation, differentiation, fusion, invasion, apoptosis, autophagy and senescence. Interestingly, tumor progression and pregnancy share many common features. The cell cycle inhibitor p21Cip1/CDKN1A (p21), being tumor suppressor or oncogene depending on its localization, plays key roles in molecular oncology by regulating different cellular processes. Although placental development depends on the precise coordination of trophoblast proliferation and differentiation, little is known about cell cycle regulators like p21. In fact, it has been reported that the expression of p21 is important for placental development and altered in PE. It is therefore tempting to propose that p21 is crucial for the functionality of trophoblasts and its deregulation could contribute to its pathogenesis. To investigate this hypothesis, the expression, localization and molecular roles of p21 in various trophoblastic cell lines as well as primary placental tissues subdivided in different stages of PE will be systematically addressed. Despite intensive research, the pathogenesis of PE is not totally understood and no therapy is currently available. It is of clinical relevance to elucidate the complexity of PE and to gain further insight into its altered molecular pathways. General findings concerning p21s role in PE are pivotal for trophoblast biology and will contribute to the understanding of this severe unpredictable and unpreventable disease. In addition, trophoblasts offer an extremely attractive model for cancer and stem cell research.