Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, 40, Daxue Road, Zhengzhou, Henan, China.
Cell Commun Signal. 2022 Oct 25;20(1):166. doi: 10.1186/s12964-022-00983-4.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) belongs to the epidermal growth factor (EGF) family of growth factors. HB-EGF and its receptors, epidermal growth factor receptor (EGFR) and HER4, are expressed in the human corpus luteum. HB-EGF has been shown to regulate luteal function by preventing cell apoptosis. Steroidogenesis is the primary function of the human corpus luteum. Steroidogenic acute regulatory protein (StAR) plays a critical role in steroidogenesis. StAR expression and progesterone (P4) production in human granulosa-lutein (hGL) cells have been shown to be upregulated by a ligand of EGFR, amphiregulin. However, whether HB-EGF can achieve the same effects remains unknown.
A steroidogenic human ovarian granulosa-like tumor cell line, KGN, and primary culture of hGL cells obtained from patients undergoing in vitro fertilization treatment were used as experimental models. The underlying molecular mechanisms mediating the effects of HB-EGF on StAR expression and P4 production were explored by a series of in vitro experiments.
Western blot showed that EGFR, HER2, and HER4 were expressed in both KGN and hGL cells. Treatment with HB-EGF for 24 h induced StAR expression but did not affect the expression of steroidogenesis-related enzymes, P450 side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase, and aromatase. Using pharmacological inhibitors and a siRNA-mediated knockdown approach, we showed that EGFR, HER4, but not HER2, were required for HB-EGF-stimulated StAR expression and P4 production. In addition, HB-EGF-induced upregulations of StAR expression and P4 production were mediated by the activation of the ERK1/2 signaling pathway.
This study increases the understanding of the physiological role of HB-EGF in human luteal functions. Video Abstract.
肝素结合表皮生长因子样生长因子（HB-EGF）属于表皮生长因子（EGF）家族的生长因子。HB-EGF 及其受体表皮生长因子受体（EGFR）和 HER4 在人黄体中表达。已经表明 HB-EGF 通过防止细胞凋亡来调节黄体功能。类固醇生成是人黄体的主要功能。类固醇生成急性调节蛋白（StAR）在类固醇生成中起着关键作用。已经表明，EGFR 的配体 Amphiregulin 上调人颗粒黄体（hGL）细胞中的 StAR 表达和孕酮（P4）产生。然而，HB-EGF 是否可以达到相同的效果尚不清楚。
使用类固醇生成的人卵巢颗粒状黄体细胞瘤系 KGN 和从接受体外受精治疗的患者中获得的 hGL 细胞的原代培养作为实验模型。通过一系列体外实验探索介导 HB-EGF 对 StAR 表达和 P4 产生的影响的潜在分子机制。
Western blot 显示 EGFR、HER2 和 HER4 在 KGN 和 hGL 细胞中均有表达。HB-EGF 处理 24 小时诱导 StAR 表达，但不影响类固醇生成相关酶、P450 侧链裂解酶、3β-羟甾脱氢酶和芳香酶的表达。使用药理学抑制剂和 siRNA 介导的敲低方法，我们表明 EGFR、HER4（而非 HER2）是 HB-EGF 刺激 StAR 表达和 P4 产生所必需的。此外，HB-EGF 诱导的 StAR 表达和 P4 产生上调是通过 ERK1/2 信号通路的激活介导的。
本研究增加了对 HB-EGF 在人黄体功能中的生理作用的理解。视频摘要。
