Abstract
Approximately 15–25% pregnant women end with miscarriage in the world. Environmental BaP (benzo(a)pyrene) and its terminal metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) may result in the dysfunctions of trophoblast cells, which might further lead to RM (recurrent miscarriage). However, potential mechanisms remain unelucidated. In this work, we identified a novel lnc-HZ05 highly expressed and a novel miR-hz05 lowly expressed in both trophoblast cells exposed to BPDE and human RM tissues. MiR-hz05 reduces FOXO3a mRNA level by weakening its mRNA stability. Lnc-HZ05 increases the expression of FOXO3a by acting as a ceRNA for miR-hz05, and then increases P21 level and reduces CDK2 level. Thus, cell cycle is arrested at G0/G1 phase and trophoblast proliferation is inhibited. Lnc-HZ05 harboring wild-type binding site for miR-hz05, but not its mutant site, could upregulate FOXO3a expression. In normal trophoblast cells, relatively less lnc-HZ05 and more miR-hz05 activate FOXO3a/P21/CDK2 pathway and promote trophoblast proliferation, giving normal pregnancy. In RM tissues and BPDE-treated human trophoblast cells, lnc-HZ05 is increased and miR-hz05 is reduced, both of which suppress this pathway and inhibit cell proliferation, and finally lead to miscarriage. Thus, lnc-HZ05 and miR-hz05 simultaneously regulate cell cycle and proliferation of BPDE-exposed trophoblast cells and miscarriage, providing new perspectives and clinical understandings in the occurrence of unexplained miscarriage.
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Acknowledgements
We acknowledge the facility supports by Central Laboratory of West China College of Public Health at Sichuan University and laboratory of the Eighth Affiliated Hospital at Sun Yat-sen University.
Funding
This work was supported by grants from the Natural Science Foundation of China (NSFC No. 82073589), the Shenzhen Science and Technology Program (No. JCYJ20210324114814038), the Futian Healthcare Research Project (No. FTWS2021009), the China Key Research and Development Program (No. 2017YFC1002002), and the Fundamental Research Funds for the Central Universities.
Natural Science Foundation of China,NSFC No. 82073589,Huidong Zhang,National Basic Research Program of China (973 Program),No. 2017YFC1002002,Huidong Zhang
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C. M. and H. Z. designed the study. C. M. performed most of the experiments. C. M., W. C., and H. Z. wrote the draft manuscript. T. L. and J. X. were responsible for animal experiments. W. H. and Z. X. contributed to the tissue preparation. P. T., M. D., and S. Z. conducted the remaining experiments.
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Mi, C., Chen, W., Liang, T. et al. Lnc-HZ05 regulates BPDE-inhibited human trophoblast cell proliferation and affects the occurrence of miscarriage by directly binding with miR-hz05. Cell Biol Toxicol 38, 1137–1157 (2022). https://doi.org/10.1007/s10565-021-09687-w
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DOI: https://doi.org/10.1007/s10565-021-09687-w