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

先兆子痫是妊娠期的一种严重疾病，是导致孕产妇和围产期死亡的最常见原因，也是导致母亲和后代长期并发症的最常见原因。PE与以改变的增殖、分化、融合、侵袭、凋亡、自噬和衰老为特征的严重胎盘细胞功能障碍相关。有趣的是，肿瘤进展和妊娠有许多共同特征。细胞周期抑制因子p21 Cip 1/CDKN 1A（p21）是一种肿瘤抑制因子或癌基因，其定位决定了其在分子肿瘤学中的重要作用。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，但对细胞周期调节因子如p21知之甚少。事实上，已经报道了p21的表达对于胎盘发育是重要的，并且在PE中改变。因此，很容易提出p21对滋养层的功能至关重要，其失调可能有助于其发病机制。为了研究这一假设，p21在各种滋养层细胞系以及在PE的不同阶段细分的原代胎盘组织中的表达，定位和分子作用将被系统地解决。尽管进行了深入的研究，但PE的发病机制尚未完全了解，目前尚无治疗方法。阐明PE的复杂性并进一步了解其改变的分子途径具有临床意义。关于p21在PE中的作用的一般发现对于滋养层生物学是关键的，并且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非常有吸引力的模型。

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.