Abstract
Transforming growth factor (TGF-β)/TGF-β receptor signal is known to promote cell migration. Up-regulation of TGF-β in serum/peritoneal fluid and increased levels of pluripotent transcription factor OCT4 in endometriotic tissues are frequently observed in patients with endometriosis. However, the mechanisms underlying how TGF-β/TGF-β receptor and OCT4 affect endometriotic cell migration still remain largely unknown. Therefore, endometriotic tissue with high cell migratory capacity were collected from patients with adenomyotic myometrium (n = 23) and chocolate cyst (n = 24); and endometrial tissue with low cell migratory capacity in normal endometrium or hyperplastic endometrium (n = 8) were collected as the controls. We found the mRNA levels of TGF-β receptor I (TGF-β RI) and OCT4 were significantly higher in the high-migratory ectopic endometriotic tissues than those of the low-migratory normal or hyperplastic endometrium. Positive correlations between TGF-β RI and OCT4, and either TGF-β RI or OCT4 with migration-related genes (SNAIL, SLUG and TWIST) regarding the mRNA levels were observed in human endometriotic tissues. TGF-βI dose-dependently increased the gene and protein levels of OCT4, SNAIL and N-Cadherin (N-CAD) and silencing of endogenous OCT4 significantly suppressed the TGF-βI-induced expressions of N-CAD and SNAIL in primary human endometriotic stromal cells and human endometrial carcinoma cell lines RL95-2 and HEC1A. Furthermore, TGF-βI significantly increased the migration ability of endometriotic cells and silencing of OCT4 dramatically suppressed the TGF-βI-induced cell migration activity evidenced by wound-closure assay, transwell assay, and confocal image of F-actin cellular distribution. In conclusion, the present findings demonstrate that the niche TGF-β plays a critical role in initiating expressions of pluripotent transcription factor OCT4 which may contribute to the ectopic endometrial growth by stimulating endometrial cell migration. These findings would be useful for developing therapeutic strategies targeting TGF-β-OCT4 signaling to prevent endometriosis in the future.
Highlights
Endometriosis is a common chronic gynecological disorder defined as the presence of ectopic endometrial tissues, primarily on the pelvic peritoneum and the ovaries [1]
We found the mRNA levels of transforming growth factor-β (TGF-β) receptor I (TGF-β RI) and OCT4 were significantly higher in the high-migratory ectopic endometriotic tissues than those of the lowmigratory normal or hyperplastic endometrium
These results demonstrated the significant increase of mRNA levels of OCT4 and TGF-β RI in ectopic endometriotic tissues
Summary
Endometriosis is a common chronic gynecological disorder defined as the presence of ectopic endometrial tissues, primarily on the pelvic peritoneum and the ovaries [1]. Several studies have reported increasing ectopic expression of stemness-related genes, including OCT4, in the endometria [15,16,17] and the upregulated OCT4 promoted the cell migration in human endometriosis [15]. The critical niche factors that regulate the OCT4 expression and cell migration in human endometriosis remain unclear. The growth factors that promote endometrial cell migration, including the transforming growth factor-β (TGF-β), are critical in human endometriosis [19, 21, 22]. As OCT4 is frequently up-regulated in endometriotic tissues [15,16,17], the present study aimed to investigate the roles of TGF-βI/TGF-β receptor Our data indicated that TGF-βI initiates the expressions of pluripotent transcription factor OCT4, and OCT4 expression may be a crucial underlying molecular mechanism of TGF-βI-stimulated cell migration in human endometriosis
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