Role of GLI1 in Hypoxia-Driven Endometrial Stromal Cell Migration and Invasion in Endometriosis

Abstract

Endometriosis (EMs) is a benign disease with the characteristics of invasion and migration, and its pathogenesis is related to hypoxia. The abnormal activation of glioma-associated oncogene homolog 1 (GLI1) plays an important role in the metastasis of multiple types of tumors. However, it is not clear whether GLI1 regulates the migration and invasion of endometrial stromal cells under hypoxic condition. Therefore, we use comprehensive analysis to explore the effects of hypoxic on GLI1 expression and their regulation on the pathogenesis of EMs. In this study, from immunohistochemistry, RT-qPCR, and western blot analysis, we discovered that the expression of hypoxia-induced factor-1α (HIF-1α) and GLI1 was significantly increased in eutopic and ectopic endometrium of patients with EMs. In human primary eutopic endometrial stromal cells (ESCs), hypoxia can increase the expression of HIF-1α and GLI1 in a time-dependent manner. And hypoxia could promote GLI1 expression in a HIF-1α-dependent manner. Moreover, data from transwell assays manifested that the migration and invasion ability of ESCs was significantly enhanced under hypoxia, and this effect could be reversed by silencing GLI1. Furthermore, the expression of MMP2 and MMP9 was also increased under hypoxia, while silencing GLI1 could reverse this event. In summary, our research verified that GLI1, which activated by hypoxia, may contribute to the migration and invasion of ESCs through the upregulation of MMP2 and MMP9 and can be a novel therapeutic target in EMs.