Activation of the TGF-β1/SOX9/SORBS2 axis drives epithelial-mesenchymal transition in the amnion of human fetal membranes in parturition

Epithelial-mesenchymal transition (EMT) in the amnion of the fetal membranes not only disrupts integrity of the membranes, but also facilitates the production of pro-labor factors, thus participating in the onset of labor. However, the triggering mechanism of EMT in the amnion is not well resolved. Resolution of the mechanism may provide novel therapeutic targets for treatment of preterm birth. Cultured primary human amnion epithelial cells were utilized to investigate the regulation and the role of SOX9 (SRY-box transcription factor 9)/SORBS2 (sorbin and SH3 domain containing 2) axis in EMT in the amnion. A mouse model was used to further study the role of SOX9/SORBS2 axis in parturition. We found that the expression of SOX9 was significantly increased in parturition in human amnion epithelial cells, where SOX9 functioned as a transcription factor driving the expression of SORBS2. Subsequently, SORBS2 prevented the linkage of E-cadherin with cytoskeletal proteins, leading to shedding of the extracellular domain of E-cadherin from the cell membrane, resulting in impairment of E-cadherin-mediated cell adhesion and the occurrence of EMT. Further investigation revealed that transforming growth factor β1 (TGF-β1) was the upstream factor driving SOX9 expression. Studies in pregnant mice demonstrated that intra-amniotic administration of vector expressing Sox9 induced preterm birth along with enhanced EMT in the fetal membranes, and these effects were blocked by shRNA (short hairpin RNA)-mediated knockdown of Sorbs2 . These data highlight that activation of the TGF-β1/SOX9/SORBS2 axis drives EMT in the amnion in parturition, and this signaling axis may offer new therapeutic targets to treat both preterm and post-term birth.