KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance.
KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance.
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DOI：
10.1038/s41598-017-04577-w
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发表时间：
2017-07-28
影响因子：
4.6
通讯作者：
Lessey BA
中科院分区：
文献类型：
--
作者：
Yoo JY;Kim TH;Fazleabas AT;Palomino WA;Ahn SH;Tayade C;Schammel DP;Young SL;Jeong JW;Lessey BA
子宫内膜异位症是一种与黄体酮抵抗和细胞增殖有关的炎症状态，导致疼痛、不孕和妊娠丢失。我们先前在患有这种疾病的不孕不育妇女的在位子宫内膜中发现了STAT3的磷酸化，导致癌基因bcl6的过度表达和缺氧诱导因子1α(HIF-1α)的稳定。在这里，我们报告了在整个月经周期中，KRAS的协同激活和组蛋白脱乙酰酶和基因沉默因子Sirtuin1(SIRT1)在子宫内膜异位症患者在位内膜中的过度表达。在PGR阳性细胞中条件激活KRAS的小鼠与对照组相比，子宫内膜中SIRT1的表达增加。在突变小鼠中，孕激素受体靶基因的表达显著下调，其中包括印度刺猬途径基因。芯片分析表明，SIRT1和BCL6共同定位于患者的细胞核中，这两种蛋白都与GLI1的启动子结合并抑制GLI1，GLI1是印度刺猬途径中孕酮作用的关键介质。在位内膜中，子宫内膜异位症患者GLI1的表达降低。这些结果提示，KRAS、SIRT1和BCL6在子宫内膜异位症患者在位内膜中协同过表达，可能参与了子宫内膜异位症的发病机制。
Endometriosis is an inflammatory condition that is associated with progesterone resistance and cell proliferation, resulting in pain, infertility and pregnancy loss. We previously demonstrated phosphorylation of STAT3 in eutopic endometrium of infertile women with this disorder leading to over-expression of the oncogene BCL6 and stabilization of hypoxia-induced factor 1 alpha (HIF-1α). Here we report coordinated activation of KRAS and over-expression of Sirtuin 1 (SIRT1), a histone deacetylase and gene silencer, in the eutopic endometrium from women with endometriosis throughout the menstrual cycle. The mice with conditional activation of KRAS in the PGR positive cells reveal an increase of SIRT1 expression in the endometrium compared to control mice. The expression of progesterone receptor target genes including the Indian Hedgehog pathway genes are significantly down-regulated in the mutant mice. SIRT1 co-localizes with BCL6 in the nuclei of affected individuals and both proteins bind to and suppress the promoter of GLI1, a critical mediator of progesterone action in the Indian Hedgehog pathway, by ChIP analysis. In eutopic endometrium, GLI1 expression is reduced in women with endometriosis. Together, these data suggest that KRAS, SIRT1 and BCL6 are coordinately over-expressed in eutopic endometrium of women with endometriosis and likely participate in the pathogenesis of endometriosis.
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影响因子：
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