Aquaporin-3 mediates ovarian steroid hormone-induced motility of endometrial epithelial cells

Abstract

STUDY QUESTIONHow does aquaporin-3 (AQP3) affect endometrial receptivity?SUMMARY ANSWERAQP3, which is regulated by the combination and estrogen (E2) and progesterone (P4), induces epithelial–mesenchymal transition (EMT) of endometrial epithelial cells.WHAT IS KNOWN ALREADYEmbryo implantation is an extremely complex process, and endometrial receptivity is essential for successful embryo implantation. Estrogen and progesterone regulate endometrial receptivity. AQP3, which is regulated by estrogen (E2), increases cell migration and invasion ability by regulating the expression of EMT-related factors and influencing the reorganization of the actin cytoskeleton.STUDY DESIGN, SIZE, DURATIONThis study investigated the pathophysiological significance of AQP3 in human endometrial function during different phases of the menstrual cycle.PARTICIPANTS/MATERIALS, SETTING, METHODSAQP3 expression levels during different phases of the menstrual cycle were measured using immunohistochemical assays. In cells of different receptivity (high-receptive RL95-2 cells and low-receptive HEC-1A cells), the expression of AQP3 was measured using western blotting, qRT-PCR and immunofluorescence assays. Activities of AQP3, and its regulation by E2 and P4, were studied through in-vitro experiments using RL95-2 cells.MAIN RESULTS AND THE ROLE OF CHANCEAQP3 expression in the mid- and late-secretory phases of the human endometrium is significantly higher than in other phases. Since AQP3 expression levels were higher in RL95-2 cells than in HEC-1A cells, mechanisms of AQP3 regulation by E2 and P4 were studied using RL95-2 cells. We provided the first report that P4 up-regulates AQP3 by directly targeting the promoter of the AQP3 gene. The up-regulation of AQP3 expression by a combination of E2 and P4 is significantly higher than that caused by either E2 or P4 alone. Together E2 and P4 promote RL95-2 cell migration and invasion by inducing EMT through AQP3. We also found that AQP3 co-localizes with ezrin and affects the formation of filopodia and lamellipodia during the E2 and P4-induced EMT process but has no effect on the expression of ezrin and F-actin.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONIt is still unclear whether AQP3 is a main regulator of endometrial receptivity or one of several factors influencing the process.WIDER IMPLICATIONS OF THE FINDINGSFurther investigation on AQP3 may contribute to a greater understanding of endometrial receptivity.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the National Natural Scientific Grants of China (No. 31570798), the Program for Liaoning Excellent Talents in University (LR2017042), the Doctoral Scientific Research Foundation of Liaoning province (201601236), and the Liaoning Provincial Program for Top Discipline of Basic Medical Sciences. There are no conflicts of interest.

Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers

“…Endometrial cancer arises from tissue lining the uterus (the endometrium) and accounts for about 95% of uterine cancers. Protein and RNA for AQPs 1, 2, 3, 5, 7 and 9 are normally expressed in endometrium, in which the AQPs are thought to be involved in fluid exchange and estrogen-mediated regulatory effects [ 200 , 201 , 202 , 203 , 204 , 205 , 206 ]. AQP1 expression in endometrial cancer has been correlated with histologic grade, extent of myometrial invasion and the likelihood of extrauterine metastasis [ 207 ], but the functional role of AQP1 in this tissue remains to be defined.…”

Transcriptomic analysis of the interaction of choriocarcinoma spheroids with receptive vs. non-receptive endometrial epithelium cell lines: an in vitro model for human implantation

“…The expression levels AQP3 and AQP4 were upregulated in Ishikawa cells after the co-culture but not in HEC-1-A. Increased expression of AQP3 has been associated with both epithelial cell migration and endometrial receptivity [53], Genes in the intersection PBK PIM1, PLK1, PLK2, PSRC1, PTTG1, RASSF2, RASSF4, SPC24, SPC25, TACC3, TRIP13, TTK, TUBB4A, TUBG2, TXNIP, USH1C, VRK1 Sterol biosynthetic process 50 7 0.04 FDFT1, FDPS, HMGCS1, IDI1, INSIG1, MSMO1, while deficiency of AQP4 leads to female subfertility in mice [54]. Other genes upregulated in Ishikawa cells upon trophoblast challenge were desmin (DES), adrenomedullin (ADM), and intermidin (ADM2).…”

Progesterone Regulates Glucose Metabolism Through Glucose Transporter 1 to Promote Endometrial Receptivity

“…Epithelial-mesenchymal transformation (EMT) has been shown to be involved in the opening of the epithelial layer (Uchida et al, 2012;Owusu-Akyaw et al, 2019). Our previous studies have shown that P4 can mediate ezrin remodeling and cytoskeletal rearrangement through aquaporin-3, affecting epithelial cell motility and participating in EMT (Cui et al, 2018). And the movement of epithelial cells is inevitably dependent on the supply of energy, which indirectly indicates that the regulation of P4 on cells is involved in glucose metabolism.…”