子宫内膜异位症发生发展中的HIF-1α及其相关信号通路

HIF-1αand Related Pathways in the Pathogenesis of Endometriosis

盆腔低氧微环境是子宫内膜异位症(endometriosis,EMs)发生、发展的重要因素之一。在低氧环境中,缺氧诱导因子1α(hypoxia-inducible factor-1 alpha,HIF-1α)参与子宫内膜组织的血管生成、炎症反应以及子宫内膜细胞的增殖凋亡、迁移侵袭和上皮-间质转化等生物学过程。研究较多的,如HIF-1α/Wnt/β-catenin、HIF-1α/长链非编码RNA(long noncoding RNA,lncRNA)UBOX5-AS1、HIF-1α/LATS1/YAP1和G蛋白耦联雌激素受体(G protein coupled estrogen receptor,GPER)/HIF-1α/基质金属蛋白酶9(matrix metalloproteinase,MMP-9)通路参与子宫内膜细胞的侵袭、迁移和上皮-间质转化;HIF-1α/转化生子因子β1(transforming growth factor-beta 1,TGF-β1)/Smad、HIF-1α/EZH2/ANTXR2通路参与异位内膜细胞的黏附;磷脂酰肌醇3激酶(phosphoinositide 3-kinase,PI3K)/蛋白激酶B(protein kinase B,AKT)/HIF-1α通路、HIF-1α/双特异性磷酸酶2(dual-specificity phosphatases 2,DUSP2)/白细胞介素6(interleukin-6,IL-6)/信号转导与转录激活因子3(signal transducer and activator of transcription 3,STAT3)和HIF-1α/微小RNA-210(miR-210)通路促进异位内膜细胞的存活、增殖;HIF-1α/miR-20a、miR-199a/HIF-1α/血管内皮生长因子(vascular endothelial growth factor,VEGF)、HIF-1α/鸡卵清蛋白上游启动子转录因子Ⅱ(chicken ovalbumin upstream promoter transcription factorⅡ,COUP-TFⅡ)/血管生成素(angiopoietin,Ang)等通路与异位内膜组织血管生成相关。最近研究还表明,EMs具有有氧糖酵解的糖代谢特点,以及低氧介导的HIF-1α稳定表达可促进子宫内膜细胞自噬水平。综述近年来HIF-1α及其相关信号通路对EMs发生、发展过程影响的研究进展,对于进一步探究EMs的发病机制具有重要意义。

The pelvic hypoxic microenvironment is an important factor of the pathogenesis and development of endometriosis(EMs),in which the induced expression of hypoxia-inducible factor-1α(HIF-1α)participates in the angiogenesis,inflammatory response,as well as the proliferation,apoptosis,migration,invasion and epithelial-mesenchymal transition(EMT)of endometrial cells.More and more studies showed that the HIF-1α/Wnt/β-catenin,HIF-1α/lncRNA UBOX5-AS1,HIF-1α/LATS1/YAP1 and GPER/HIF-1α/MMP-9 pathway participated in the migration,invasion and EMT;HIF-1α/TGF-β1/Smad and HIF-1α/EZH2/ANTXR2 in the cell adhesion;PI3K/AKT/HIF-1α,HIF-1α/DUSP2/IL-6/STAT3 and HIF-1α/miR-210 pathway in the cell survive and proliferation;HIF-1α/miR-20a,miR-199a/HIF-1α/VEGF and HIF-1α/COUP-TFⅡ/Ang pathway in the angiogenesis of ectopic endometrial tissue.The recent studies also showed the characteristics of aerobic glycolysis in ectopic endometrial tissue and the autophage activated by HIF-1α.In this review,we summarized the effects of HIF-1αand its related signaling pathways in the EMs for further exploring the pathogenesis of EMs.