Activation of the MAPK/ERK Cell-Signaling Pathway in Uterine Smooth Muscle Cells of Women With Adenomyosis

Abstract

We investigated whether the myometrium might be intrinsically different in women with adenomyosis. We studied whether the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs) and phosphoinositide 3-kinase/mammalian target of rapamycin/AKT (PI3K/mTOR/AKT) cell-signaling pathways, implicated in the pathogenesis of endometriosis, might also be activated in uterine smooth muscle cells (uSMCs) of women with adenomyosis and measured the production of reactive oxygen species (ROS), proinflammatory mediators that modulate cell proliferation and have been shown to activate the MAPK/ERK pathway in endometriosis. The uSMC cultures were derived from myometrium biopsies obtained during hysterectomy or myomectomy in women with adenomyosis and controls with leiomyoma. Proliferation of uSMCs and in vitro activation of the MAPK/ERK cell-signaling pathway were increased in women with adenomyosis compared to controls. The activation of the PI3K/mTOR/AKT pathway was not significant. The ROS production and ROS detoxification pathways were not different between uSMCs of women with adenomyosis and controls suggesting an ROS-independent activation of the MAPK/ERK pathway. Our results also provide evidence that protein kinase inhibitors and the rapanalogue temsirolimus can control proliferation of uSMCs in vitro suggesting an implication of the MAPK/ERK and the PI3K/mTOR/AKT pathways in proliferation of uSMCs in women with adenomyosis and leiomyomas.

Transcriptome sequencing of adenomyosis eutopic endometrium: A new insight into its pathophysiology

“…25 The ERK/ MAPK signalling pathway was associated with the proliferation of uterine smooth muscle cells in the women with adenomyosis. 26 The overlapping of our findings with the previous studies may reflect the universal mechanisms underlying the adenomyosis and the reliability of our data.…”

“…The IL‐6 signalling pathway was significantly increased in endometrial stromal cells after in vitro coculture with macrophage in adenomyosis which might play a role in the formation of ectopic tissues in adenomyosis . The ERK/MAPK signalling pathway was associated with the proliferation of uterine smooth muscle cells in the women with adenomyosis . The overlapping of our findings with the previous studies may reflect the universal mechanisms underlying the adenomyosis and the reliability of our data.…”

MicroRNA-17 downregulates expression of the PTEN gene to promote the occurrence and development of adenomyosis

“…When lesions in the myometrium exhibit limited nodules, the condition is also referred to as adenomyoma. The etiology and molecular mechanisms of AM remain unclear (2). AM usually occurs in mothers >40 years old, with an incidence of 15-70% among this population sub-group (3).…”

Bioinformatics strategy for the screening of key genes to differentiate adenomyosis from endometriosis (Review)

“…We found that the survival and apoptosis-related genes were upregulated or downregulated in the previous studies cited. Thus, the proliferation-and growth-related genes, including IGF1 (16)(17)(18)(19), IGF2 (19), vascular endothelial growth factor (VEGF) (40)(41)(42), hepatocyte growth factor (HGF) (43)(44)(45), nerve growth factor (NGF) (46)(47)(48), platelet-derived growth factor (PDGF) (16,49), epidermal growth factor receptor (EGFR) (16,17,49,50), fibroblast growth factor 2 (FGF2) (49,51,52) and mechanistic target of rapamycin kinase (mTOR) (53,54), were upregulated in both the ectopic and eutopic endometria from subjects with adenomyosis compared with the eutopic endometria from women without adenomyosis, while the anti-apoptotic or autophagy-related genes, such as BCL2 apoptosis regulator (BCL2) (38,(55)(56)(57), beclin 1 (BECN1) (58,59) and programmed cell death 4 (PDCD4) (60,61), were much higher in the ectopic and eutopic endometria than in the control endometria. Furthermore, the decreased expression of BCL2 associated X, apoptosis regulator (BAX) has been observed in adenomyosis, suggesting that the downregulation of apoptotic cell death machinery is a hallmark of adenomyosis (39).…”

“…x) MTOR. Endometrial cells proliferate, migrate and survive by modulating the phosphatidylinositol 3-kinase (PI3K)/AKT/p-mTOR signaling pathway (53). The expression of p-mTOR has been shown to be higher in the ectopic endometrium than in the eutopic endometrium of patients with endometriosis or adenomyosis (53,54).…”