Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway
Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway
复制标题
DOI：
10.1093/molehr/gav039
复制
发表时间：
2015-10-01
影响因子：
4
通讯作者：
Choi, Jung-Hye
中科院分区：
文献类型：
--
作者：
Ahn, Ji-Hye;Choi, Youn Seok;Choi, Jung-Hye
尽管有证据表明瘦素可能在子宫内膜异位症的发病机制中发挥作用，但瘦素在子宫内膜异位症细胞迁移和侵袭中的具体功能还没有得到很好的表征。本研究旨在探讨瘦素对人子宫内膜异位症细胞迁移、侵袭及基质金属蛋白酶表达水平的影响。我们发现瘦素以剂量依赖的方式刺激子宫内膜异位细胞(11Z、12Z和22B)的迁移和侵袭。瘦素受体(OBR)siRNA显著抑制瘦素诱导的11Z和12Z细胞的迁移和侵袭。特异性明胶酶(MMP2和MMP9)抑制剂SB-3CT可显著抑制瘦素诱导的细胞迁移和侵袭。此外，瘦素还可诱导11Z和12Z细胞中基质金属蛋白酶-2的表达和酶活性增加。使用siRNA和一种抑制剂(GM6003)选择性地抑制基质金属蛋白酶-2，削弱了瘦素刺激子宫内膜异位症细胞迁移和侵袭的能力，提示基质金属蛋白酶-2在瘦素诱导的迁移和侵袭中起重要作用。Janus Kinase 2信号转导和转录激活因子3(JAK2/STAT3)抑制剂(AG490)显著抑制瘦素诱导的子宫内膜异位症细胞的迁移、侵袭和基质金属蛋白酶-2的表达。此外，细胞外信号调节的激酶抑制剂PD98059中和了瘦素促进迁移和侵袭的作用。综上所述，这些结果提示瘦素可能通过OBR依赖的JAK2/STAT3信号通路上调基质金属蛋白酶-2，从而促进子宫内膜异位症细胞的迁移和侵袭能力。
Despite evidence that leptin may play a role in the pathogenesis of endometriosis, the specific function of leptin in the migration and invasion of endometriotic cells is not well characterized. In this study, we investigated the effect of leptin on the migration, invasion and matrix metalloproteinase (MMP) expression levels of human endometriotic cells. We found that leptin stimulated the migration and invasion of endometriotic cells (11Z, 12Z and 22B) in a dose-dependent manner. Leptin receptor (ObR) siRNA significantly inhibited the migration and invasion induced by leptin in 11Z and 12Z cells. Leptin-induced migration and invasion were significantly attenuated by pretreatment with SB-3CT, a specific gelatinase (MMP-2 and MMP-9) inhibitor. In addition, leptin-induced increases in the mRNA and protein expression and enzyme activity of MMP-2 in 11Z and 12Z cells. Selectively inhibiting MMP-2 using siRNA and an inhibitor (GM6003), impaired the ability of leptin to stimulate the migration and invasion of endometriotic cells, suggesting that MMP-2 plays an essential role in leptin-induced migration and invasion. Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) inhibitor (AG490) significantly inhibited the migration, invasion and MMP-2 expression induced by leptin in endometriotic cells. Furthermore, the Extracellular signal-Regulated Kinase inhibitor PD98059 neutralized the migration and invasion promoting effects of leptin. Taken together, these results suggest that leptin may contribute to the migration and invasion abilities of endometriotic cells via the up-regulation of MMP-2 through an ObR-dependent JAK2/STAT3 signaling pathway.