Abstract：
Endometriosis is an estrogen-dependent and progesterone-resistant gynecological inflammatory disease of reproductive-age women. Progesterone resistance, loss of progesterone receptor -B (PR-B) in the stromal cells of the endometrium, is one of the hallmarks of endometriosis and a major contributing factor for infertility in endometriosis patients. Loss of PR-B in the stromal cells of the endometriotic lesions poses resistance to the success of progesterone-based therapy. The working hypothesis is that PR-B is hypermethylated and epigenetically silenced, and inhibition of AKT and ERK1/2 pathways will decrease the hypermethylation, reverse the epigenetic silencing, and restore the expression of PR-B via DNA methylation and histone modification mechanisms in the endometriotic lesions. The objectives are to (i) determine the effects of dual inhibition of AKT and ERK1/2 pathways on the expression of PR-B and DNA methylation and histone modification protein machinery in the endometriotic lesions and (ii) identify the underlying epigenetic mechanisms of PR-B restoration in the endometriotic lesions. The results indicate that dual inhibition of AKT and ERK1/2 pathways decreases the hypermethylation, reverses the epigenetic silencing, and restores the expression of PR-B via DNA methylation and H3K9 and H3K27 methylation mechanisms in the endometriotic lesions or endometriotic stromal cells of human origin. These results support the novel concept that restored expression of PR-B in the endometriotic lesions and endometrium may improve the clinical outcome of progesterone therapy in endometriosis patients.
摘要：
子宫内膜异位症是育龄期妇女的一种雌激素依赖性和抗孕激素的妇科炎症性疾病。孕酮抗性,子宫内膜基质细胞中孕激素受体-B（PR-B）的丢失，是子宫内膜异位症的标志之一，也是子宫内膜异位症患者不孕的主要因素。子宫内膜异位病变基质细胞中PR-B的丢失对基于孕激素的治疗的成功构成了抵抗。工作假设是PR-B是高甲基化和表观遗传沉默的，AKT和ERK1/2通路的抑制将减少过度甲基化，逆转表观遗传沉默，并通过DNA甲基化和组蛋白修饰机制恢复子宫内膜异位病变中PR-B的表达。目的是(i)确定AKT和ERK1/2途径的双重抑制对子宫内膜异位病变中PR-B和DNA甲基化和组蛋白修饰蛋白机制的表达的影响,以及(ii)确定子宫内膜异位病变中PR-B恢复的潜在表观遗传机制。结果表明，AKT和ERK1/2通路的双重抑制降低了过度甲基化，逆转表观遗传沉默，并通过DNA甲基化和H3K9和H3K27甲基化机制在人来源的子宫内膜异位病变或子宫内膜间质细胞中恢复PR-B的表达。这些结果支持了一个新的概念，即恢复子宫内膜异位病变和子宫内膜中PR-B的表达可能会改善子宫内膜异位症患者孕激素治疗的临床结果。
