PABPC1 regulates EOPE pathogenesis through modulating TMBIM4 mRNA expression and stability

Preeclampsia (PE), a rare complication with a high incidence and mortality rate, causes tremendous mental and physical impairment to pregnant women. Emerging studies have identified that PE was primarily induced by inadequate trophoblast migration and invasion. Poly(A) Binding Protein Cytoplasmic 1 (PABPC1) is a critical modulator of mRNA translation and stability, with established role in modulating proliferation, apoptosis, and invasion of tumor cells. Transmembrane BAX Inhibitor Motif Containing 4 (TMBIM4), which negatively regulates apoptosis, is downregulated in placental tissues of patients with early-onset preeclampsia (EOPE). Notably, 3'UTR motif of TMBIM4 mRNA contains PABPC1 binding site. Here, we investigated the functional role of PABPC1 on regulating proliferation and invasion of trophoblast cells, and how PABPC1 modulated mRNA stability of TMBIM4. HTR-8/SVneo cells transfected with silencing or overexpressed PABPC1 plasmid were applied as the in vitro model. The results revealed that PABPC1 facilitated cell proliferation, migration, and invasion as well as inhibited apoptosis. Moreover, Sprague Dawley rats were received intraperitoneal lipopolysaccharides administration at 40 μg/kg on gestational days 14.5, 15.5, and 16.5. Upregulated PABPC1 ameliorated elevated blood pressure and severe kidney impairment. Furthermore, for the rescue experiments, the effect of PABPC1 on boosting cell proliferation and invasion was blocked by silencing TMBIM4. More interestingly, according to RIP-qPCR and dual luciferase reporter assays, PABPC1 enhanced TMBIM4 expression through enhancing its mRNA stability via binding to its 3'UTR. Taken together, PABPC1 suppressed EOPE development through boosting trophoblast proliferation and invasion by elevating TMBIM4 mRNA stability. Our findings firstly elucidated the vital effect of PABPC1 on EOPE pathogenesis and highlighted that PABPC1 upregulation might be developed as a promising strategy for EOPE treatment.