Down-Regulating Hexokinase 2 Inhibits Proliferation of Endometrial Stromal Cells Through a Noncanonical Pathway Involving Phosphorylated-STAT1 in Endometriosis

Background: Endometriosis is a benign gynecologic disease that causes chronic pelvic pain, dysmenorrhea and infertility and shares several characteristics with malignant tumors, afflicting women of reproductive age. Hexokinase 2 (HK2) plays a pivotal role as the first rate-limiting enzyme in the metabolic glycolysis pathway, and its abnormal elevation in tumors is associated with tumor genesis and metastasis. However, the expression and role of HK2 in endometriosis remain unclear.Methods: We sequenced the primary endometrial stromal cells from patients with endometrioma and adopted immunohistochemistry, quantitative real-time PCR and western blot to determine the expression of HK2. Then wound healing assays, cell invasion assays, cell proliferation assays were performed to explore the functions of HK2 in endometrial stromal cells. Furthermore, mice models of endometriosis were recruited to observe the effects of HK2 inhibitors in vivo. Lastly, glycolysis metabolism detection and transcriptome sequencing were carried out in HK2-knockdown endometrial stromal cells to analyze the mechanism of HK2 affecting cell function.Results: Endometriotic stromal cells displayed active glycolysis metabolism and elevated expression of HK2. Downregulating HK2 reduced the migration, invasion and proliferation capacity of endometrial stromal cells. Knockdown of HK2 induced upregulation of signal transducer and activator of transcription 1 (STAT1) and their phosphorylation to attenuate the proliferation of endometrial stromal cells.Conclusions: HK2 was associated with the migration, invasion and proliferation of endometrial stromal cells, which might provide new insights into the pathogenesis and treatment of endometriosis.