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首页> 外文期刊>Human Reproduction >Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis.
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Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis.

机译：子宫内膜异位症患者异位子宫内膜基质细胞中Ras / Raf / MAPK和RhoA / ROCKII信号通路的异常激活。

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BACKGROUND Enhanced proliferation and survival of eutopic endometrial cells from patients with endometriosis compared with healthy women is associated with abnormal activation of extra-cellular signal-regulated kinases 1 and 2 (ERK1/2). Given the role of Ras/Raf/mitogen-activated protein kinase (MAPK) and RhoA/ROCKII signalling pathways in the regulation of cell proliferation and migration, we analysed their possible roles in endometriosis. METHODS Primary eutopic endometrial stromal cells of patients with endometriosis (Eu-hESC, n= 16) and endometriosis-free controls (Co-hESC, n= 14) were harvested and subjected to proliferation and migration assays as well as kinase activity assays and immunoblot analysis of proteins from the Ras/Raf/MAPK and RhoA/ROCKII signalling pathways. Effects of ROCKII (Y-27632) and MAPK (U0126) inhibitors or siRNA knockdown of ROCKII, Raf-1 and B-Raf were analysed. RESULTS The proliferation rate of Eu-hESC was 54% higher than Co-hESC. Eu-hESC also displayed a 75% higher migration rate than Co-hESC. Eu-hESC displayed higher levels of ERK phosphorylation (83%) and p27 expression (61%) and lower levels of Raf-1 protein (47%) compared with controls. In addition to an inhibitory effect on cell proliferation, ROCKII knockdown led to significant down-regulation of cyclinD1 and p27 but did not affect ERK phosphorylation. Down-regulation of Raf-1 by siRNA was dispensable for cell proliferation control but led to an increase in ROCKII activity and a decrease in cell migration. B-Raf was shown to act as a regulator of hESC proliferation by modulating cellular ERK1/2 activity and cyclinD1 levels. Eu-hESC displayed 2.4-fold higher B-Raf activity compared with Co-hESC and therefore exhibit abnormally activated Ras/Raf/MAPK signalling. CONCLUSIONS We show that the same molecular mechanisms operate in Co- and Eu-hESC. The differences in cell proliferation and migration between both cell types are likely due to increased activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in cells from endometriosis patients.
机译：背景技术与健康妇女相比，子宫内膜异位症患者的异位子宫内膜细胞的增殖和存活增强与细胞外信号调节激酶1和2（ERK1 / 2）的异常激活有关。鉴于Ras / Raf /丝裂原活化蛋白激酶（MAPK）和RhoA / ROCKII信号通路在调节细胞增殖和迁移中的作用，我们分析了它们在子宫内膜异位症中的可能作用。方法收集子宫内膜异位症患者（Eu-hESC，n = 16）和无子宫内膜异位对照（Co-hESC，n = 14）的原位异位子宫内膜间质细胞，并进行增殖和迁移测定以及激酶活性测定和免疫印迹Ras / Raf / MAPK和RhoA / ROCKII信号通路的蛋白质分析。分析了ROCKII（Y-27632）和MAPK（U0126）抑制剂的作用或ROCKII，Raf-1和B-Raf的siRNA敲低。结果Eu-hESC的增殖率比Co-hESC高54％。 Eu-hESC的迁移率也比Co-hESC高75％。与对照组相比，Eu-hESC显示出较高水平的ERK磷酸化（83％）和p27表达（61％）和较低水平的Raf-1蛋白（47％）。除了抑制细胞增殖外，ROCKII的抑制还导致cyclinD1和p27的显着下调，但不影响ERK的磷酸化。 siRNA对Raf-1的下调对于细胞增殖控制是必不可少的，但会导致ROCKII活性的增加和细胞迁移的减少。 B-Raf通过调节细胞ERK1 / 2活性和cyclinD1水平显示出作为hESC增殖的调节剂。与Co-hESC相比，Eu-hESC的B-Raf活性高2.4倍，因此表现出异常激活的Ras / Raf / MAPK信号传导。结论我们证明在Co-和Eu-hESC中存在相同的分子机制。两种细胞类型之间细胞增殖和迁移的差异可能是由于子宫内膜异位症患者细胞中Ras / Raf / MAPK和RhoA / ROCKII信号通路的激活增加所致。

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