Liu Hengwei, Zhang Zhibing, Xiong Wenqian, Zhang Ling, Xiong Yao, Li Na, He Haitang, Du Yu, Liu Yi
Department of Obstetrics and GynecologyUnion Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Obstetrics and GynecologyVirginia Commonwealth University, Richmond, Virginia, USA.
Reproduction. 2017 Jun;153(6):809-820. doi: 10.1530/REP-16-0643. Epub 2017 Mar 27.
Endometriosis is a benign gynecological disease that shares some characteristics with malignancy like migration and invasion. It has been reported that both hypoxia-inducible factor-1α (HIF-1α) and autophagy were upregulated in ectopic endometrium of patients with ovarian endometriosis. However, the crosstalk between HIF-1α and autophagy in the pathogenesis of endometriosis remains to be clarified. Accordingly, we investigated whether autophagy was regulated by HIF-1α, as well as whether the effect of HIF-1α on cell migration and invasion is mediated through autophagy upregulation. Here, we found that ectopic endometrium from patients with endometriosis highly expressed HIF-1α and autophagy-related protein LC3. In cultured human endometrial stromal cells (HESCs), autophagy was induced by hypoxia in a time-dependent manner and autophagy activation was dependent on HIF-1α. In addition, migration and invasion ability of HESCs were enhanced by hypoxia treatment, whereas knockdown of HIF-1α attenuated this effect. Furthermore, inhibiting autophagy with specific inhibitors and Beclin1 siRNA attenuated hypoxia triggered migration and invasion of HESCs. Taken together, these results suggest that HIF-1α promotes HESCs invasion and metastasis by upregulating autophagy. Thus, autophagy may be involved in the pathogenesis of endometriosis and inhibition of autophagy might be a novel therapeutic approach to the treatment of endometriosis.
子宫内膜异位症是一种良性妇科疾病，具有一些与恶性肿瘤相似的特征，如迁移和侵袭。据报道，在卵巢子宫内膜异位症患者的异位内膜中，缺氧诱导因子-1α（HIF-1α）和自噬均上调。然而，HIF-1α与自噬在子宫内膜异位症发病机制中的相互作用仍有待阐明。因此，我们研究了自噬是否受HIF-1α调控，以及HIF-1α对细胞迁移和侵袭的影响是否通过自噬上调介导。在此，我们发现子宫内膜异位症患者的异位内膜高度表达HIF-1α和自噬相关蛋白LC3。在培养的人子宫内膜基质细胞（HESC）中，缺氧以时间依赖性方式诱导自噬，且自噬激活依赖于HIF-1α。此外，缺氧处理增强了HESC的迁移和侵袭能力，而敲低HIF-1α减弱了这种作用。此外，用特异性抑制剂和Beclin1 siRNA抑制自噬减弱了缺氧触发的HESC迁移和侵袭。综上所述，这些结果表明HIF-1α通过上调自噬促进HESC的侵袭和转移。因此，自噬可能参与子宫内膜异位症的发病机制，抑制自噬可能是治疗子宫内膜异位症的一种新的治疗方法。
