Department of Obstetrics and Gynecology, Yang-Pu Center Hospital, Shanghai, China.
Department of Obstetrics and Gynecology, Yang-Pu Center Hospital, Shanghai, China.
Transl Res. 2014 Mar;163(3):232-41. doi: 10.1016/j.trsl.2013.11.008. Epub 2013 Nov 20.
In this study, we explored the role of estrogen-mediated activation of stromal fibroblasts in the pathogenesis of uterine fibroid in patients. We isolated uterine fibroids and surrounding smooth muscle from patients and separated fibroblasts using immunomagnetic beads. We also measured the expression levels of estrogen receptors in fibroblasts and examined cell proliferation, expressions of fibroblast activation protein (FAP), extracellular matrix (ECM) (fibronectin, laminin, collagen I), growth factors (transforming growth factor-β, insulin-like growth factor-1), and cell proliferation pathway stimulated by estrogen. We also silenced the expression of FAP by RNA interference and analyzed the expression levels of these markers before and after E2 stimulation. Finally, we also investigated the effect of activated fibroblast supernatant on cell proliferation of fibroblasts, smooth muscle cells, and fibroid cells. We found that fibroblasts in uterine fibroid were activated, and the expression levels of estrogen receptors from fibroid cells were higher than those from smooth muscle cells. After estrogen stimulation, the proliferation activity of fibroblast was enhanced, and the expression of FAP, ECM, and growth factors was increased; the signaling pathway involved in cell proliferation was also activated. Interestingly, the activated fibroblast supernatant stimulation can promote cell proliferation. Silencing of FAP expression could inhibit the E2-mediated biological effects. In conclusion, estrogen promotes proliferation of uterine fibroids through the activation of fibroblasts, thus, activated fibroblasts may play an important role in the pathogenesis of uterine fibroids, which could be targeted in future for the treatment of uterine fibroid.
在这项研究中，我们探讨了雌激素介导的基质成纤维细胞激活在患者子宫肌瘤发病机制中的作用。我们从患者中分离出子宫肌瘤和周围的平滑肌，并使用免疫磁珠分离成纤维细胞。我们还测量了成纤维细胞中雌激素受体的表达水平，并检查了细胞增殖、成纤维细胞激活蛋白（FAP）、细胞外基质（ECM）（纤连蛋白、层粘连蛋白、胶原 I）、生长因子（转化生长因子-β、胰岛素样生长因子-1）的表达水平以及雌激素刺激的细胞增殖途径。我们还通过 RNA 干扰沉默 FAP 的表达，并在 E2 刺激前后分析这些标记物的表达水平。最后，我们还研究了激活的成纤维细胞上清液对成纤维细胞、平滑肌细胞和纤维瘤细胞增殖的影响。我们发现子宫肌瘤中的成纤维细胞被激活，且纤维瘤细胞中的雌激素受体表达水平高于平滑肌细胞。雌激素刺激后，成纤维细胞的增殖活性增强，FAP、ECM 和生长因子的表达增加；涉及细胞增殖的信号通路也被激活。有趣的是，激活的成纤维细胞上清液刺激可以促进细胞增殖。沉默 FAP 表达可以抑制 E2 介导的生物学效应。总之，雌激素通过激活成纤维细胞促进子宫肌瘤的增殖，因此，激活的成纤维细胞可能在子宫肌瘤的发病机制中发挥重要作用，这可能成为未来治疗子宫肌瘤的靶点。
