The Role Of FGF2 In The Development Of Adenomyosis And The Mechanism

BackgroudAdenomyosis is a prevalent, benign gynaecologic disorder in women. In adenomyosis, the endometrial tissue, including stromal and glandular tissue, invades the myometrium, causing myometrial inflammation and hypertrophy and resulting in debilitating pelvic pain and abnormal uterine bleeding. Adenomyosis can also interfere with normal implantation and cause infertility. However, the mechanism of this disease is still unclear.Fibroblast growth factor 2 (FGF2) is one of the first confirmed angiogenesis-related growth factors. FGF2 mediates its biological effects by binding to FGF receptors (FGFRs), which then activate downstream signalling cascades, of which the MAPK/ERK1/2 pathway is the most important. Activated ERK1/2 plays an important role in target cells by phosphorylating downstream signalling molecules and triggering a spectrum of responses, including caryomitosis, differentiation, proliferation, and migration. Recent studies found different feedback inhibitors of the FGF2/MAPK/ERK signalling pathway, such as the dual-specificity phosphatase 6 (Dusp6) and Sef. These molecules play important roles in inhibiting the FGF2/MAPK/ERK signalling pathway.Adenomyosis is an oestrogen-dependent disease. It always occurs in fertile women, and the postmenopausal ectopic endometrium gradually atrophies. This suggests that this disease is associated with levels of oestrogen. Abnormal expression of FGF2 and its receptor has been observed in aadenomyosis, whereas, as the feedback inhibitors of this pathway, Dusp6 and Sef was rarely reported in this disease.ObjectiveIn previous studies, we found that the expressions of Dusp6 and Sef were down-regulated in endometrial epithelial cells in patients with adenomyosis. In the current study, we investigated the roles of 17β-estradiol and FGF2 in the regulating the expression of Dusp6 and Sef in endometrial epithelial cells in patients with adenomyosis. In addition, we investigated the pathways that might be involved.MethodsEndometria from 20 patients with adenomyosis and 19 controls without adenomyosis were employed in this study. Through western blot, we investigated the roles of 17β-estradiol and FGF2 in the regulating the expression of Dusp6 and Sef in different endometrial epithelial cells and the pathways that might be involved.Results1. Dusp6 and Sef were down-regulated in epithelial cells in patients with adenomyosis (n=20)compared with controls(n=19) (p<0.05)2. FGF2 and 17β-estradiol significantly activated MAPK-dependent ERK phosphorylation in endometrial epithelial cells.3. FGF2 and 17β-estradiol increased Dusp6 and Sef expressions via MAPK/ERK signalling in normal epithelial cells (n=19) (p<0.01).4. FGF2 and 17β-estradiol decreased the expressions of Dusp6 and Sef in epithelial cells in adenomyosis(n=20)(p<0.05).Conclusions1. Dusp6 and Sef were down-regulated in epithelial cells in patients with adenomyosis compared with normal endometrial epithelial cells. Decreased expressions of Dusp6 and Sef may be involved in the genesis and development of adenomyosis.2. FGF2 and 17β-estradiol could reduce the expressions of Dusp6 and Sef in epithelial cells from patients with adenomyosis. The down-regulations of Dusp6 and Sef may be related to 17β-estradiol and FGF2 induced abnormal activation of ERK signaling pathways and the abnormal activated signal pathway may play a significant role in the incidence of adenomyosis.