STX2 Promotes Trophoblast Growth, Migration, and Invasion Through Activation of the PI3K-AKT Pathway in Preeclampsia

Yan Li; Xian-Li Sun; Chun-Ling Ma; Chao Li; Ying Zhan; Wen-Ting Li; Can Li; Yi-Hao Wang

doi:10.3389/fcell.2021.615973

STX2 Promotes Trophoblast Growth, Migration, and Invasion Through Activation of the PI3K-AKT Pathway in Preeclampsia

Front Cell Dev Biol. 2021 Jul 6:9:615973. doi: 10.3389/fcell.2021.615973. eCollection 2021.

Authors

Yan Li¹, Xian-Li Sun², Chun-Ling Ma¹, Chao Li¹, Ying Zhan¹, Wen-Ting Li¹, Can Li¹, Yi-Hao Wang³

Affiliations

¹ Department of Obstetrics and Gynaecology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.
² Department of Obstetrics and Gynecology, Qingdao Women and Children's Hospital, Qingdao University, Qingdao, China.
³ Department of Pain Management, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.

Abstract

Objectives: Abnormal trophoblast behaviors during pregnancy contribute to the development of preeclampsia (PE). Syntaxin2 (STX2) has been shown to be a crucial epithelial mediator in numerous diseases. However, the functions of STX2 and the mechanisms underlying its role in PE remain largely unknown. The aim of this study was to explore the role of STX2 on trophoblast biology and unravel the molecular mechanisms that contribute to the development and progression of PE.

Materials and methods: We first compared the expression of STX2 in placental tissues from women with PE and women with normal pregnancies. Then, we investigated the role of STX2 on trophoblast proliferation, migration and invasion in HTR-8/SVneo and primary human trophoblast cells by loss or gain of function experiments. In addition, co-immunoprecipitation, pulldown and immunofluorescence assays were performed to investigate the co-localization of STX2 with other proteins, and to help clarify the mechanisms underlying STX2-mediated functions on trophoblasts.

Results: We demonstrated that STX2 expression was downregulated in placental tissues of women with PE compared with those from normal pregnancies. Loss and gain of function experiments further confirmed a role for STX2 in cell proliferation, migration and invasion in trophoblasts. By co-immunoprecipitation, pulldown and immunofluorescence co-localization assays, we revealed that STX2 selectively interacted with p85, a subunit of PI3K, and directly recruited p85 to the cytomembrane, thereby activating the AKT signaling pathway. We further demonstrated that the AKT activation was abolished by the use of a PI3K inhibitor (LY294002), which negatively affected STX2-mediated functions on trophoblasts.

Conclusion: All together, our findings point to a crucial role for STX2 in PE progression. Our new insights also suggest that STX2 may be a potential diagnostic tool and a novel therapeutic target for treating PE.

Keywords: AKT; PI3K; preeclampsia; syntaxin2; trophoblast.