Objective

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.

Design

Case-control laboratory study.

Setting

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 S1P₂, S1P₃, and S1P₅ 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 S1P₂. The profibrotic action of activin A was abolished when SK1/2 were inhibited or S1P_2/3 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.

中文翻译：

---

子宫肌瘤中的鞘氨醇 1-磷酸信号传导：对激活素 A 促纤维化作用的影响

客观的

探讨 1-磷酸鞘氨醇 (S1P) 信号传导与平滑肌瘤之间的联系，以及可能的 S1P 串扰与激活素 A 的纤维化作用。

设计

病例对照实验室研究。

设置

大学研究所和大学医院。

患者

子宫肌瘤患者（n = 26）。

干预措施

从接受子宫肌瘤切除术或全子宫切除术的患者中获得平滑肌瘤和正常子宫肌层的组织标本。

主要结果测量

在匹配的平滑肌瘤/子宫肌层标本和细胞群中评估了参与 S1P 代谢、S1P 受体和 S1P 转运蛋白 Spns2 的酶的 mRNA 水平的表达。在平滑肌瘤细胞系中评估了抑制 S1P 代谢和信号传导对激活素 A 诱导的纤维化作用的影响。

结果

与邻近的子宫肌层相比，平滑肌瘤中负责 S1P 形成的酶、鞘氨醇激酶 (SK) 1 和 2 以及 S1P ₂、S1P ₃和 S1P ₅受体的表达显着增加。在平滑肌瘤细胞中，而不是在子宫肌层细胞中，激活素 A 增加了 SK1、SK2 和 S1P _{2 的}mRNA 表达水平。当 SK1/2 被抑制或 S1P _2/3被阻断时，激活素 A 的促纤维化作用被消除。最后，S1P 自身增加了平滑肌瘤中纤维化标志物（纤连蛋白、胶原蛋白 1A1）和激活素 A 的 mRNA 水平，但在子宫肌层细胞中没有。

结论

该研究表明，S1P 信号在子宫肌瘤中失调并参与激活素 A 诱导的纤维化，为子宫肌瘤治疗开辟了新的前景。