Department of Experimental and Clinical Biomedical Sciences "M. Serio," University of Florence, Florence, Italy.
Department of Experimental and Clinical Medicine, Faculty of Medicine, Università Politecnica delle Marche, Ancona, Italy.
Fertil Steril. 2021 Jun;115(6):1576-1585. doi: 10.1016/j.fertnstert.2020.12.022. Epub 2021 Jan 23.
To explore the link between sphingosine 1-phosphate (S1P) signaling and leiomyoma and the possible S1P cross-talk with the fibrotic effect of activin A.
Case-control laboratory study.
University institute and university hospital.
PATIENT(S): Patients with uterine fibroids (n = 26).
INTERVENTIONS(S): Tissue specimens of leiomyoma and normal myometrium were obtained from patients undergoing myomectomy or total hysterectomy.
MAIN OUTCOME MEASURE(S): Expression of mRNA levels of the enzyme involved in S1P metabolism, S1P receptors, and S1P transporter Spns2 was evaluated in matched leiomyoma/myometrium specimens and cell populations. The effects of inhibition of S1P metabolism and signaling was evaluated on activin A-induced fibrotic action in leiomyoma cell lines.
RESULT(S): The expression of the enzymes responsible for S1P formation, sphingosine kinase (SK) 1 and 2, and S1P, S1P, and S1P receptors was significantly augmented in leiomyomas compared with adjacent myometrium. In leiomyoma cells, but not in myometrial cells, activin A increased mRNA expression levels of SK1, SK2, and S1P. The profibrotic action of activin A was abolished when SK1/2 were inhibited or S1P were blocked. Finally, S1P augmented by itself mRNA levels of fibrotic markers (fibronectin, collagen 1A1) and activin A in leiomyomas but not in myometrial cells.
CONCLUSION(S): This study shows that S1P signaling is dysregulated in uterine fibroids and involved in activin A-induced fibrosis, opening new perspectives for uterine fibroid treatment.
探讨鞘氨醇 1-磷酸（S1P）信号与子宫肌瘤之间的联系，以及 S1P 与激活素 A 的纤维化作用之间可能存在的交叉对话。
病例对照实验室研究。
大学研究所和大学医院。
子宫肌瘤患者（n=26）。
从接受子宫肌瘤切除术或全子宫切除术的患者中获取子宫肌瘤和正常子宫肌组织标本。
在匹配的子宫肌瘤/子宫肌组织标本和细胞群中评估参与 S1P 代谢、S1P 受体和 S1P 转运体 Spns2 的酶的 mRNA 水平表达。评估 S1P 代谢和信号抑制对子宫肌瘤细胞系中激活素 A 诱导的纤维化作用的影响。
与相邻的子宫肌层相比，形成 S1P 的酶，即鞘氨醇激酶（SK）1 和 2，以及 S1P、S1P 和 S1P 受体的表达在子宫肌瘤中显著增加。在子宫肌瘤细胞中，但不在子宫肌细胞中，激活素 A 增加了 SK1、SK2 和 S1P 的 mRNA 表达水平。当抑制 SK1/2 或阻断 S1P 时，激活素 A 的促纤维化作用被消除。最后，S1P 本身可增加子宫肌瘤中纤维化标志物（纤连蛋白、胶原 1A1）和激活素 A 的 mRNA 水平，但不会增加子宫肌层细胞中的水平。
本研究表明 S1P 信号在子宫肌瘤中失调，并参与激活素 A 诱导的纤维化，为子宫肌瘤的治疗开辟了新的前景。
