Increased α2-6 sialylation of endometrial cells contributes to the development of endometriosis

Abstract

Endometriosis is a disease characterized by implants of endometrial tissue outside the uterine cavity and is strongly associated with infertility. Focal adhesion of endometrial tissue to the peritoneum is an indication of incipient endometriosis. In this study, we examined the effect of various cytokines that are known to be involved in the pathology of endometriosis on endometrial cell adhesion. Among the investigated cytokines, transforming growth factor-β1 (TGF-β1) increased adhesion of endometrial cells to the mesothelium through induction of α2-6 sialylation. The expression levels of β-galactoside α2-6 sialyltransferase (ST6Gal) 1 and ST6Gal2 were increased through activation of TGF-βRI/SMAD2/3 signaling in endometrial cells. In addition, we discovered that terminal sialic acid glycan epitopes of endometrial cells engage with sialic acid-binding immunoglobulin-like lectin-9 expressed on mesothelial cell surfaces. Interestingly, in an in vivo mouse endometriosis model, inhibition of endogenous sialic acid binding by a NeuAcα2-6Galβ1-4GlcNAc injection diminished TGF-β1-induced formation of endometriosis lesions. Based on these results, we suggest that increased sialylation of endometrial cells by TGF-β1 promotes the attachment of endometrium to the peritoneum, encouraging endometriosis outbreaks.

Variation of total serum sialic acid concentration in postmenopausal women

“…SA also plays a key role in the fertility maturation and activation of sperm cells (17)(18)(19), as well as development of the embryo (20,21). Some studies have found a link between serum estrogen levels and SA on the surface of endometrial cells or changes that determine the pathological state in endometrial cancer or endometriosis (22,23).…”

Variability of serum IgG sialylation and galactosylation degree in women with advanced endometriosis

“…In contrast, they did not observe any difference in the expression of sialic acid α2,3-linked. Authors concluded, that the mechanisms of altered sialylation during endometriosis development, especially those affecting the adhesion between endometrial cells and peritoneal mesothelial cells, are still unclear 16 . It has been reported that the glycoproteins levels are increased in peritoneal fluid, serum, and eutopic endometrium of women with endometriosis 38 , 52 .…”

“…The ‘gold diagnostic standard’ for endometriosis identification is laparoscopic inspection with histologic confirmation after biopsy, however, the correlation between clinical symptoms and disease stage is poor, and invasive testing carries required anaesthesia and surgical skills and produces potential risk of complications 11 , 12 . Many studies focus on searching for biochemical markers with high sensitivity and specificity for non-invasive diagnostics or screening of endometriosis 11 – 13 as well as aim better understanding molecular mechanisms responsible for disease development 14 – 16 . Proper identification of endometriosis is still problematic in gynaecologic practice, therefore extensive research for new biomarkers give hope for more accurate diagnostics, especially in the advanced stages of the disease.…”

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

“…Altered expression of sialylglycans is associated with epithelial-mesenchymal transition (EMT), an essential step for tumor progression and metastasis [53]. Transforming growth factor-β (TGF-β) induced EMT process caused upregulation of various sialyltransferases such as ST3GAL1, ST3GAL2, ST6GAL1, ST6GAL2, ST8SIA1, ST8SIA2, and ST8SIA4 [54][55][56][57][58][59][60][61]. The upregulation of those sialyltransferases resulted in accumulation of sialylglycans on the cell surface, assisting tumor cells in surviving and metastasis.…”