Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea.
Int J Med Sci. 2022 Oct 3;19(12):1779-1786. doi: 10.7150/ijms.75203. eCollection 2022.
Uterine leiomyoma is the most common benign tumor in women of reproductive age, and it can cause infertility. The growth of uterine leiomyoma is mediated by various steroids and growth factors. The purpose of this study was to evaluate the expression of various growth factors in uterine leiomyoma. Additionally, comparing the effects of existing medication and specific growth factor inhibitors on leiomyoma and the normal myometrium, we aimed to see the potential of transforming growth factor-beta (TGF-β) inhibitors and vascular endothelial growth factor (VEGF) inhibitors as therapeutic drugs for uterine leiomyoma. This study included uterine leiomyoma samples from 12 patients who underwent hysterectomy by laparoscopy or laparotomy at Seoul St. Mary's Hospital between May 2016 and March 2018. Normal myometrium and uterine leiomyoma tissue were obtained from each patient and the expression of growth factors was compared using immunohistochemical staining. After the primary culture of normal myometrial and leiomyoma cells, cell viability was evaluated following treatment with 100 nM ulipristal acetate (UPA) and mifepristone for 48 h. Western blot analysis was performed to determine the protein expression of each growth factor. Cell viability was determined following treatment with a 10-µM TGF-β inhibitor (LY364947) and a 5-µM VEGF inhibitor (axitinib) for 24 h in cultured normal myometrium and leiomyoma cells. Immunohistochemical staining revealed the significantly higher intensity of TGF-β and VEGF in the leiomyoma tissue than in the normal myometrium (P < 0.05). Mifepristone treatment decreased VEGF expression by 62% in the leiomyoma cells (P < 0.05). According to the cell counting kit-8 (CCK-8) assay, cell viability was decreased after UPA, mifepristone, TGF-β1 inhibitor, and VEGF inhibitor treatments in the normal myometrium and leiomyoma tissue. The effects of the TGF-β1 inhibitor significantly differed between normal myometrium and leiomyoma tissue, with a greater decrease in cell survival in the leiomyoma tissue (P < 0.05). Post-hoc analysis showed that the TGF-β1 and VEGF inhibitors had a greater inhibitory effect on leiomyoma tissue compared with that of UPA. TGF-β and VEGF inhibitors significantly decreased the viability of uterine leiomyoma cells, showing stronger effects than the conventional drug, UPA. TGF-β1 inhibitors affect both leiomyoma tissue and the normal uterus; thus, targeted local treatment rather than systemic treatment should be considered.
子宫肌瘤是育龄妇女中最常见的良性肿瘤，可导致不孕。子宫肌瘤的生长由各种类固醇和生长因子介导。本研究旨在评估子宫肌瘤中各种生长因子的表达。此外，通过比较现有药物和特定生长因子抑制剂对子宫肌瘤和正常子宫平滑肌的作用，我们旨在探讨转化生长因子-β（TGF-β）抑制剂和血管内皮生长因子（VEGF）抑制剂作为治疗子宫肌瘤的潜在药物。
该研究纳入了 2016 年 5 月至 2018 年 3 月期间在首尔圣玛丽医院通过腹腔镜或剖腹手术行子宫切除术的 12 名患者的子宫肌瘤样本。从每位患者中获取正常子宫平滑肌和子宫肌瘤组织，并通过免疫组织化学染色比较生长因子的表达。在对正常子宫平滑肌和肌瘤细胞进行原代培养后，用 100 nM 乌利司他（UPA）和米非司酮处理 48 小时后，评估细胞活力。用 10 μM TGF-β抑制剂（LY364947）和 5 μM VEGF 抑制剂（axitinib）处理培养的正常子宫平滑肌和肌瘤细胞 24 小时后，进行 Western blot 分析以确定每种生长因子的蛋白表达。
免疫组织化学染色显示，与正常子宫平滑肌相比，肌瘤组织中 TGF-β和 VEGF 的强度明显更高（P < 0.05）。米非司酮治疗使肌瘤细胞中的 VEGF 表达降低了 62%（P < 0.05）。根据细胞计数试剂盒（CCK-8）检测，在正常子宫平滑肌和肌瘤组织中，UPA、米非司酮、TGF-β1 抑制剂和 VEGF 抑制剂处理后，细胞活力均降低。TGF-β1 抑制剂的作用在正常子宫平滑肌和肌瘤组织之间存在显著差异，肌瘤组织中细胞存活率的降低更为显著（P < 0.05）。事后分析显示，TGF-β1 和 VEGF 抑制剂对肌瘤组织的抑制作用大于 UPA。
TGF-β 和 VEGF 抑制剂显著降低了子宫肌瘤细胞的活力，与常规药物 UPA 相比，其效果更强。TGF-β1 抑制剂对肌瘤组织和正常子宫均有影响；因此，应考虑局部靶向治疗而不是全身治疗。
