Hypomethylation of IL6ST promotes development of endometriosis by activating JAK2/STAT3 signaling pathway

Endometriosis is a chronic inflammatory disorder characterized by presence of endometrial tissue outside the uterine cavity. Immunohistochemical analysis (IHC) revealed markedly elevated expression of IL6ST in endometrial tissue of patients with ovarian endometriosis. Level of methylation of IL6ST is diminished in patients with endometriosis, whereas level of mRNA expression is markedly elevated by RT-PCR. Cell Counting Kit-8, Transwell, Terminal deoxynucleotidyl transferase dUTP nick end labeling assays substantiated endometrial stromal cells stably transfected with 3*FLAG-IL6ST plasmid exhibited enhanced viability, augmented invasive capacity, and notable reduction in apoptosis rates. Furthermore, IL6ST facilitated progression of endometriosis by activating mitogen-activated protein kinase 9/Signal Transducer and Activator of Transcription 3 signaling pathway. Western blot analysis revealed significantly elevated protein levels of p-JAK2/JAK2, p-STAT3/STAT3, HIF-1α, and VEGF in IL6ST overexpression group. Conversely, JAK2/STAT3 inhibitor WP1066 had markedly reduced p-JAK2 and p-STAT3 protein levels in IL6ST overexpression group. Inhibiting JAK2/STAT3 signaling pathway had mitigating effect on proliferative and invasive enhancement of endometrial stromal cells, as well as inhibition of apoptosis induced by IL6ST. These findings offer novel potential targets and strategies for the treatment of endometriosis.