BAP1 Overexpression Inhibited the PI3K-AKT-mTOR Pathway via Deubiquitinating PTEN and Suppressing Trophoblastic EMT

抄録

Preeclampsia (PE) causes fetal growth restriction. Although trophoblastic epithelial-mesenchymal transition (EMT) dysfunction has been reported to be associated with PE, the underlying pathological mechanisms have not been fully elucidated. BRCA1-associated protein 1 (BAP1) is suggested to play a crucial role in regulating trophoblast biological activities, yet, the exact molecular mechanisms by which BAP1 regulates EMT have not been investigated. Thus, this study explored the role of BAP1 overexpression in EMT and its underlying mechanism. Invasion of JEG-3 and HTR-8/SVneo cells was used to assess the role of BAP1 in PE. BAP1 expressing vectors, and short-hairpin RNA targeting BAP1 were constructed, and multiple analytical assays were performed, such as CCK-8, Western blotting, qPCR, trans-well assay, invasion, and migration assay, to depict the underlying mechanism of BAP1 in EMT. Our results showed that silencing BAP1 in human normal trophoblast HTR8/SVneo cells promoted their proliferation, invasion, and migration, and the expressions of E-cadherin, Bax, cleaved caspase 3, and PTEN were downregulated while N-cadherin, vimentin, Bcl-2, p-PI3K, p-Akt, and p-mTOR were upregulated. On the other hand, overexpressing BAP1 in human choriocarcinoma JEG-3 cells suppressed their proliferation, invasion, and migration, and the protein expressions of E-cadherin, Bax, and cleaved caspase 3 and PTEN were upregulated, while the expressions of N-cadherin, Bcl-2, vimentin, p-PI3K, p-Akt, and p-mTOR were downregulated. Mechanistically, it was found that BAP1 overexpression suppressed the PI3K/Akt/mTOR signaling pathway via deubiquitinating phosphatase and tensin homolog (PTEN). Our findings indicate a potential therapeutic target of PE.