Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis

Iveta Yotova, I Y Yotova, P Quan, Ping Quan, N Leditznig, Nadja Leditznig, U Beer, R Wenzl, René Wenzl, Walter Tschugguel, W Tschugguel
Human Reproduction · 2011 · vol. 26(4) , pp. 885–897 · doi:10.1093/humrep/der010 · PMID:21303778 · W2168910626
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Endometrial stromal cells from endometriosis patients exhibit increased proliferation and migration due to the abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signaling pathways.

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Abstract

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.

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Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometrium Gene Expression Regulation, Enzymologic MAP Kinase Signaling System raf Kinases ras Proteins rhoA GTP-Binding Protein rho-Associated Kinases Stromal Cells Cell Movement Cell Proliferation Endometriosis Endometrium Enzyme Activation Enzyme Inhibitors Enzyme Inhibitors Female Humans Phosphorylation raf Kinases

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