Hoffmann Marta, Fiedor Elżbieta, Ptak Anna
Department of Physiology and Toxicology of Reproduction, Chair of Animal Physiology, Institute of Zoology, Jagiellonian University, Krakow, Poland.
Department of Physiology and Toxicology of Reproduction, Chair of Animal Physiology, Institute of Zoology, Jagiellonian University, Krakow, Poland
Reprod Sci. 2016 Nov;23(11):1600-1608. doi: 10.1177/1933719116648214. Epub 2016 Jun 2.
Accumulating evidence suggests that leptin is expressed at higher levels in obese women and stimulates cell migration in epithelial cancers. However, the biology of ovarian cancer is different from others, mainly due to the production of estrogens because of the involvement of ovarian tissue, which is the main source of estrogens; as a result, the levels are at least 100- to 1000-fold higher than normal circulating levels. Thus, ovarian cancer tissues are exposed to 17β-estradiol, which promotes ovarian cancer cell migration and may modulate the effect of other hormones. Therefore, this study investigated the effects of 17β-estradiol (1 nmol/L) with leptin (1-40 ng/mL) at physiological levels, on the migration of OVCAR-3 and SKOV-3 ovarian cancer cells, and the expression levels and activity of metalloproteinases (MMPs) 2 and 9. Here, we found that leptin stimulated ovarian cancer cell line migration, which is mediated via the expression and activity of MMP-9 in the OVCAR-3 but not in the SKOV-3 cells. After the administration of 17β-estradiol and leptin, we observed antagonistic effects of 17β-estradiol on leptin-induced OVCAR-3 cell migration and MMP-9 expression and activity. Moreover, the antagonistic effect of 17β-estradiol on leptin-induced cancer cell migration was reversed by pretreatment of the cells with the phosphatidylinositol 3-kinase (PI3K) pathway inhibitor. Taken together, our results, for the first time, show that in ovarian cancer cells ObR/ER, 17β-estradiol has an antagonistic effect on leptin-induced cell migration as well as MMP-9 expression and activity, which is mediated by the PI3K pathway.
越来越多的证据表明，瘦素在肥胖女性体内表达水平较高，并能刺激上皮癌中的细胞迁移。然而，卵巢癌的生物学特性与其他癌症不同，这主要是由于卵巢组织参与雌激素的产生，而卵巢组织是雌激素的主要来源；因此，其水平比正常循环水平至少高100至1000倍。因此，卵巢癌组织会接触到17β-雌二醇，它能促进卵巢癌细胞迁移，并可能调节其他激素的作用。因此，本研究调查了生理水平下17β-雌二醇（1 nmol/L）与瘦素（1 - 40 ng/mL）对OVCAR - 3和SKOV - 3卵巢癌细胞迁移以及金属蛋白酶（MMPs）2和9的表达水平及活性的影响。在此，我们发现瘦素刺激卵巢癌细胞系迁移，这是通过OVCAR - 3细胞中MMP - 9的表达和活性介导的，而在SKOV - 3细胞中则不然。给予17β-雌二醇和瘦素后，我们观察到17β-雌二醇对瘦素诱导的OVCAR - 3细胞迁移以及MMP - 9表达和活性具有拮抗作用。此外，用磷脂酰肌醇3 -激酶（PI3K）途径抑制剂预处理细胞可逆转17β-雌二醇对瘦素诱导的癌细胞迁移的拮抗作用。综上所述，我们的结果首次表明，在卵巢癌细胞中ObR/ER，17β-雌二醇对瘦素诱导的细胞迁移以及MMP - 9表达和活性具有拮抗作用，这是由PI3K途径介导的。
