N-Myc and STAT Interactor Is A Endometriosis Suppressor Gene

Endometriosis is an estrogen-dependent inflammatory disease. A pivotal contributor to endometriosis is the estrogen receptor beta (ERß), which drives the condition by impeding cell death through interferon (IFN) signaling. One noteworthy component of this cascade is the N-myc and STAT Interactor (NMI), an interferon alpha (IFNa) target gene whose expression is repressed in endometriotic lesions compared to normal endometrium. This repression is particularly pronounced in stromal cells, mediated by ERß. The results of Western blot analyses, comparing IFNa-treated and untreated cells, demonstrate that IFNa treatment triggers cell death signaling, including apoptosis and necroptosis, in endometrial stromal cells. Intriguingly, NMI knockdown (KD) obstructed IFNa-induced cell death signaling in human endometrial stromal cells. Moreover, NMI KD amplified non-canonical IFNa pathways, such as ß-Catenin/GSK3ß and PI3K/AKT signaling, in endometrial stromal cells following IFNa treatment. RNA sequencing analyses unveiled that NMI KD augmented the expression of genes responsible for cell-cell adhesion and extracellular structural organization in IFNa-independent manners. These findings suggest that NMI KD plays an indispensable role in enhancing the adhesion and invasion of endometriotic cells during endometriosis progression. In summary, NMI functions as an endometriosis suppressor gene in endometriotic stromal cells, curbing the advancement of endometriosis. This intricate interplay of ERß, IFNa signaling, and NMI offers novel insights into the mechanisms governing endometriosis development. Overall design: To investigate the role of NMI in endometriosis progression, we generated immortalized human endometriotic stromal cell lines (WT) and their NMI knockdown (KD) derivatives using shRNA (NMI KD). We then treated the cells with vehicle (PBS with 0.1% Bovine Serum Albumin) or IFNa (invitrogen, 500ut/ml) for 24 hours. Then, we analyzed and compared gene expression profiling of RNA-Seq data obtained from WT and NMI KD cells in the presence or absence of IFNa.