糖皮质激素与转化生长因子β1协同上调PAI-1的机制及可能的生物学意义

Glucocorticoid (GC) usually exerts its effects through the glucocorticoid receptor (GR). GC bound to GR which acts as a transcription factor, the glucocorticoid-receptor-complex is translocated to the nucleus and binds after dimerization to GC response elements (GREs) to regulate target genes. TGF-β can rapidly activate the transcription of a set of specific genes mediated through two types of transmembrane serine/threonine kinase receptors (type I and type II), and the highly conserved Smad family of proteins has been identified as intracellular signal transducers to relay the TGF-β signal to the nucleus. TGF-β and glucocorticoid signaling pathways interact both positively and negatively in regulating a variety of physiological and pathological processes.Plasminogen activator inhibitor type-1 (PAI-1) is a target gene of TGF-β which can also be regulated by GC. As the primary inhibitor of urokinase-type and tissue-type plasminogen activator (PAs), PAI-1, is generally regarded as a profibrotic factor because it retards ECM degradation by inhibiting the degrading enzymes. PAI-1 also plays an important role in the process of rat ovulation and as one of the marker for quality of ovum. We found that GC and TGFβ1 synergistically increase PAI-1 expression in ovarian cancer cells. Based on this issue, we will further explore the effect of GC and TGFβ1 on the expression of PAI-1 in normal ovarian cells and normal ovarian tissues and its possible mechanism and biological significance. The study can help us understand the interaction between GC / GR and TGFβ1 signal pathway and its effect on ovarian physiological function and biological behavior of ovarian cancer. There are important theoretical value and clinical significance.

糖皮质激素(GC)和转化生长因子β（TGFβ）在各自的受体介导下，通过激活信号转导通路，调节基因的表达产生生物学效应。两条通路间存在复杂的相互作用，根据组织细胞类型的不同和调节基因的不同，表现为相互拮抗和协同效应。纤溶酶原激活物抑制剂（PAI-1）是纤溶酶原激活物（PAs）的生理抑制剂，能抑制纤维蛋白和细胞外基质降解，从而促进基质的沉积和细胞的粘附。PAI-1对卵巢的正常功能和排卵机制中在时间和空间上的协调一致也起重要作用。本课题拟在前期发现GC和TGFβ1能协同上调卵巢癌细胞中PAI-1表达的基础上，进一步探讨在正常卵巢细胞和组织中GC和TGFβ对PAI-1表达的影响及其可能的机制与病理生理学意义。通过本课题的研究，有助于我们进一步了解GC/GR和TGFβ1信号通路的相互作用，以及这种相互作用对卵巢生理功能和卵巢癌生物学行为的影响，有重要的理论价值和临床意义。

糖皮质激素（GC）和转化生长因子β1（TGFβ1）在调节细胞增殖、分化、细胞外基质的形成以及肿瘤的发生发展中起着重要的作用。纤溶酶原激活物抑制剂1(PAI-1)是一种组织相关纤溶酶原激活物抑制剂，能抑制细胞外基质降解，在肿瘤进展中发挥重要作用。已经证明PAI-1是TGFβ1内源性靶基因，TGFβ1能通过经典的Smad通路诱导其表达，GC也能上调PAI-1的表达。作为肿瘤微环境中的重要成分，GC和TGFβ1对PAI-1的协同作用还不清楚。因此本课题主要在卵巢癌中探讨了GC和TGFβ1对PAI-1的协同调节作用和协同调节的机制以及这种协同调节作用对卵巢癌进展的影响，取得了如下研究结果：.我们研究发现，GC和TGFβ1在卵巢癌细胞中可以协同上调PAI-1的表达，该作用发生在转录水平，通过GR介导。TGFβ1通过激活p38MAPK和ERK信号通路, 提高配体依赖性的GR丝氨酸211位点的磷酸化水平，显著增强GR的转录活性，进而所致PAI-1表达的协同增加。进一步的研究表明，增加了的PAI-1促进了卵巢癌细胞与细胞外基质的粘附能力，这可能与卵巢癌化疗药耐药有关。以上结果揭示了GC/GR信号通路和TGFβ1信号通路相互作用，通过改变GR的磷酸化从而改变靶基因表达的新机制。