Abstract
Increasing evidences have shown that pregnant women might miscarry after exposure with environmental BaP (benzo(a)pyrene). Additionally, BPDE (benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide), the ultimate metabolite of BaP, could induce dysfunctions of human trophoblast cells. However, it is rarely correlated between miscarriage and trophoblast dysfunctions. Moreover, their underlying mechanisms are still largely unidentified. In this study, a novel lncRNA (long non-coding RNA), lnc-HZ08, was identified to be highly expressed in human recurrent miscarriage (RM) tissues and in BPDE-treated human trophoblast cells. Lnc-HZ08 acts as a RNA scaffold to interact with both PI3K and its ubiquitin ligase CBL (Cbl proto-oncogene), enhances their protein interactions, and promotes PI3K ubiquitin degradation. In RM tissues and BPDE-treated trophoblast cells, DNA methylation level in lnc-HZ08 promoter region was reduced, which promotes estrogen receptor 1 (ER)–mediated lnc-HZ08 transcription. Subsequently, this upregulated lnc-HZ08 downregulated PI3K level, suppressed PI3K/p-AKT/p-P21/CDK2 pathway, and thus weakened proliferation, migration, and invasion of human trophoblast cells, which further induces miscarriage. These results may provide novel scientific and clinical insights in the occurrence of unexplained miscarriage.
Graphical abstract
A novel lncRNA (lnc-HZ08) regulates the functions of human trophoblast cells and affects miscarriage. Lnc-HZ08 promotes PI3K ubiquitin degradation by enhancing CBL and PI3K interactions, downregulates PI3K/p-AKT/p-P21/CDK2 pathway, and weakens proliferation, migration, and invasion of trophoblast cells. BPDE exposure reduces the DNA methylation level in lnc-HZ08 promoter region and promotes estrogen receptor 1 (ER)–mediated lnc-HZ08 transcription. The suppressed PI3K/p-AKT/p-P21/CDK2 pathway regulated by increased lnc-HZ08 is associated with miscarriage. These results provide novel insights in the occurrence of unexplained miscarriage.
Graphical Headlights
• Lnc-HZ08 downregulates PI3K/p-AKT/p-P21/CDK2 pathway to suppress proliferation, migration, and invasion of human trophoblast cells, and affects miscarriage.
• Lnc-HZ08 acts as a RNA scaffold to enhance the protein interaction of PI3K and its ubiquitin ligase CBL, which increases PI3K ubiquitination and degradation.
• Lnc-HZ08 transcription is associated with DNA methylation on its promoter region and transcription factor ER.
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The datasets used or analyzed in the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors acknowledge financial support from the Natural Science Foundation of China (NSFC No. 82073589), the China Key Research and Development Program (No. 2017YFC1002002), and the Fundamental Research Funds for the Central Universities. We acknowledge the facility supports by Central Laboratory of the Eighth Affiliated Hospital at Sun Yat-sen University and West China College of Public Health at Sichuan University.
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This study received financial support from the Natural Science Foundation of China (NSFC No. 82073589), the China Key Research and Development Program (No. 2017YFC1002002), and the Fundamental Research Funds for the Central Universities.
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J. X., T. L., and H. Z. designed the study. J. X., T. L., and H. Z. performed most of the experiments. J. X., T. L., and H. Z. wrote the draft manuscript. J. Z. and R. W. were responsible for animal experiments. C. M. and Z. X. contributed to the tissue preparation. W. H., P. T., and W. C. conducted partial experiments. Z. X. and P. T. contributed to the linguistic editing.
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Xie, J., Liang, T., Zhao, J. et al. Lnc-HZ08 regulates BPDE-induced trophoblast cell dysfunctions by promoting PI3K ubiquitin degradation and is associated with miscarriage. Cell Biol Toxicol 38, 291–310 (2022). https://doi.org/10.1007/s10565-021-09606-z
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DOI: https://doi.org/10.1007/s10565-021-09606-z