Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma
Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma
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DOI：
10.1159/000055275
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发表时间：
1999-01-01
期刊：
影响因子：
3.5
通讯作者：
Maruo, T
中科院分区：
文献类型：
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作者：
Matsuo, H;Kurachi, O;Maruo, T
子宫平滑肌瘤出现于生殖期，绝经后消退，提示卵巢激素依赖性生长潜能。为了揭示性甾体激素调控平滑肌瘤生长的分子机制，我们研究了性甾体激素是否会影响平滑肌瘤细胞的增殖。由于表皮生长因子（EGF）已被证明可以介导雌激素的作用，并在调节平滑肌瘤生长中发挥关键作用，我们也研究了性类固醇对平滑肌瘤细胞中EGF和EGF受体（EGF- r）表达的影响。在平滑肌瘤细胞培养中，添加雌二醇（E-2, 10 ng/ml）或黄体酮（P-4, 100 ng/ml）均可增加细胞中增殖细胞核抗原（PCNA）的表达，而在正常子宫肌瘤细胞培养中，添加E-2可增强细胞中PCNA的表达，而P-4则没有。免疫印迹分析显示，平滑肌瘤细胞含有免疫反应性EGF， P-4处理导致细胞中EGF表达增加，而E-2处理导致细胞中EGF表达降低。相比之下，E-2处理增加了培养的平滑肌瘤细胞中EGF-R的表达，而P-4则没有。这些结果表明，P-4上调平滑肌瘤细胞中PCNA和EGF的表达，而E-2上调平滑肌瘤细胞中PCNA和EGF- r的表达。因此，可以想象，P-4和E-2共同作用，通过诱导EGF和EGF- r的表达来刺激平滑肌瘤细胞的增殖潜能。我们还发现，细胞凋亡抑制基因产物bcl-2蛋白在平滑肌瘤中相对于正常肌层中大量表达，并且bcl-2蛋白在平滑肌瘤细胞中的表达被P-4上调，而被E-2下调。因此，我们认为P-4可能也通过诱导平滑肌瘤细胞中的bcl-2蛋白参与了平滑肌瘤的生长。子宫平滑肌瘤细胞中Bcl-2蛋白的丰富表达可能是子宫平滑肌瘤相对于正常子宫肌层生长增强的分子基础之一。
Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. In order to characterize the molecular mechanism of sex steroidal regulation of leiomyoma growth, we examined whether sex steroids could influence the proliferation of leiomyoma cells. As epidermal growth factor (EGF) has been shown to mediate estrogen action and play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on EGF and EGF receptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cells, the addition of either estradiol (E-2; 10 ng/ml) or progesterone (P-4; 100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (PCNA) expression in the cells, whereas in cultures of normal myometrial cells, the addition of E-2 augmented PCNA expression in the cells, but P-4 did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreactive EGF and that P-4 treatment resulted in an increase in EGF expression in the cells, whereas E-2 treatment resulted in a lower EGF expression in the cells. By contrast, E-2 treatment augmented EGF-R expression in cultured leiomyoma cells, but P-4 did not. These results indicate that P-4 upregulates the expression of PCNA and EGF in leiomyoma cells, whereas E-2 upregulates the expression of PCNA and EGF-R in those cells. It is, therefore, conceivable that P-4 and E-2 act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF and EGF-R expression. We also found that bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometrium and that Bcl-2 protein expression in leiomyoma cells was upregulated by P-4, but downregulated by E-2 It seems, therefore, likely that P-4 may also participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells. The abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of a leiomyoma relative to that of normal myometrium in the uterus.