RAS/MEK/ERK Signal Pathway Regulates NF-κBp65 to Promote the Invasion and Proliferation of Endometrial Stromal Cells in Endometriosis

Abstract

Objectives: The aim of this study is to investigate the relationship between the Nuclear factor-kappa B (NF-κBp65) and RAS/MEK/ERK signaling cascade and their influence on the proliferation and invasion of endometrial stromal cells. Design: A prospective case control study was carried out. The endometriotic ovarian cyst wall was examined as a case whereas endometrial tissue obtained during endometrial curettage and non-endometriotic ovarian cyst wall were examined as controls (n = 15). Methods: To explore the relationship between RAS/MEK/ERK and NF-κB pathway, we firstly detected the expression of RAS, MEK, ERK and NF-κBp65 in the control endometrium and eutopic/ectopic endometrium with endometriosis. Then their affection on the proliferative and invasive abilities of endometrial stromal cells was analyzed by CCK-8 and Trans-well and verified the upstream and downstream relationship between RAS/MEK/ERK and NF-κB signaling pathway cascade by Western blot. Results: The results revealed that the expression levels of MAPK kinase-dependent molecules RAS, MEK, ERK and NF-κBp65 in eutopic/ectopic endometrial stromal cells of patients with endometriosis were significantly higher than those in the control group (p < 0.05). When the expression of MEK, ERK and NF-κBp65 were respectively silenced, the proliferation and invasion of eutopic endometrial stromal cells were all significantly suppressed. They all participated in the progress of endometriosis. Of note, the expression of NF-κBp65 protein was obviously inhibited after respectively suppressing ERK, MEK and RAS/MEK/ERK signaling pathway (p < 0.05). However, the expression of RAS, MEK and ERK has no change after NF-κBp65 was silenced by small interfering RNA (p > 0.05). Conclusions: The NF-κBp65 is regulated by the RAS/MEK/ERK signal pathway to promote the proliferation and invasion of eutopic endometrial stromal cells. Its inhibitors provide the selection of multiple potential targets and different joint intervention approaches for non-hormonal therapy for endometriosis.