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European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Pre-Eclampsia | Research

Low m6A modification-mediated upregulation of PLAC8 promotes trophoblast cell invasion and migration in preeclampsia

Authors: Yajuan Zhang, Xiaoguang Guo, Zhimin Chen, Ruixia Guo

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

Background

The main symptoms of preeclampsia (PE), a specific ailment that develops during pregnancy, are proteinuria and hypertension. The pathological root of the onset and progression of PE is widely regarded as abnormal placental trophoblast cell function. This study aimed to look into the character and mechanism of Placenta-specific 8 (PLAC8) in trophoblast cell invasion and migration.

Methods

Expressions of PLAC8 and AlkB homologue 5 (ALKBH5) were examined by western blot and quantitative real-time PCR. The m6A level of PLAC8 mRNA was detected by methylated RNA Immunoprecipitation. Using Transwell experiments, cell invasion and migration were examined. The enzyme-linked immunosorbent assay was utilized to analyze the MMP-2 and MMP-9 secretion levels. RNA pull-down and RNA immunoprecipitation were conducted to detect the binding between ALKBH5 and PLAC8.

Results

In PE tissue and hypoxia-treated HTR-8/SVneo cells, levels of ALKBH5 and PLAC8 were increased, and PLAC8 m6A methylation levels were decreased. There was a positive correlation between PLAC8 and ALKBH5 expression in clinical tissues. In addition, overexpressing PLAC8 promoted HTR-8/SVneo cell migration and invasion, and so as the levels of MMP-2 and MMP-9; while interference with PLAC8 reduced the migration and invasion of hypoxia-treated HTR-8/SVneo cells, and so as the levels of MMP-2 and MMP-9. Moreover, the PLAC8 mRNA’s m6A modification site was GAACU (Position 1449, Site 2). Increased levels of MMP-2 and MMP-9, as well as migration and invasion of HTR-8/SVneo cells exposed to hypoxia, were all facilitated by the m6A Site2 mutation. Furthermore, ALKBH5 could bind to PLAC8, reduce its m6A modification, and promote its expression.

Conclusion

High-expressed ALKBH5 inhibits the m6A level of PLAC8 mRNA and promotes PLAC8 expression, while PLAC8 overexpression can promote hypoxia-induced invasion and migration of HTR-8/Svneo cells, indicating its potential protective function in PE.
Literature
1.
Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012;36(1):56–9.CrossRefPubMed
2.
Suo M, Sun Y, Yang H, Ji J, He Y, Dong L, Wang Y, Zhang Y, Zhang Y, Hao M. miR-183–5p suppressed the invasion and migration of HTR-8/SVneo trophoblast cells partly via targeting MMP-9 in preeclampsia. 2020. Biosci Rep. https://​doi.​org/​10.​1042/​BSR20192575.
3.
Zhang J, Guo S, Piao HY, Wang Y, Wu Y, Meng XY, Yang D, Zheng ZC, Zhao Y. ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1. J Physiol Biochem. 2019;75(3):379–89.CrossRefPubMedPubMedCentral
4.
Zhu Z, Qian Q, Zhao X, Ma L, Chen P. N(6)-methyladenosine ALKBH5 promotes non-small cell lung cancer progress by regulating TIMP3 stability. Gene. 2020;731:144348.CrossRefPubMed
5.
Burton GJ, Redman CW, Roberts JM, Moffett A. Pre-eclampsia: pathophysiology and clinical implications. BMJ. 2019;366:l2381.CrossRefPubMed
6.
7.
Galaviz-Hernandez C, Stagg C, de Ridder G, Tanaka TS, Ko MS, Schlessinger D, Nagaraja R. Plac8 and Plac9, novel placental-enriched genes identified through microarray analysis. Gene. 2003;309(2):81–9.CrossRefPubMed
8.
Ghanem N, Salilew-Wondim D, Gad A, Tesfaye D, Phatsara C, Tholen E, Looft C, Schellander K, Hoelker M. Bovine blastocysts with developmental competence to term share similar expression of developmentally important genes although derived from different culture environments. Reproduction. 2011;142(4):551–64.CrossRefPubMed
9.
10.
Barragán-Zúñiga LJ, Marchat LA, Carrasco-Wong I, Blanco-Castaneda R, Salas-Pacheco JM, Simental-Mendia LE, Correa-Ramírez MM, Sosa-Macías M, Gutiérrez J, Galaviz-Hernandez C. Evaluation of the PLAC8 gene in Mexican women with and without preeclampsia and obesity. Front Med. 2022;9:795309.CrossRef
11.
Boulias K, Greer EL. Biological roles of adenine methylation in RNA. Nat Rev Genet. 2023;24(3):143–60.CrossRefPubMed
12.
Wang J, Gao F, Zhao X, Cai Y, Jin H. Integrated analysis of the transcriptome-wide m6A methylome in preeclampsia and healthy control placentas. PeerJ. 2020;8:e9880.CrossRefPubMedPubMedCentral
13.
Qu J, Yan H, Hou Y, Cao W, Liu Y, Zhang E, He J, Cai Z. RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential. J Hematol Oncol. 2022;15(1):8.CrossRefPubMedPubMedCentral
14.
Guo Y, Song W, Yang Y. Inhibition of ALKBH5-mediated m(6) A modification of PPARG mRNA alleviates H/R-induced oxidative stress and apoptosis in placenta trophoblast. Environ Toxicol. 2022;37(4):910–24.CrossRefPubMed
15.
Wang L, Yang J, Wang H, Wang W, Liang X. Highly expressed ribosomal protein L34 predicts poor prognosis in acute myeloid leukemia and could be a potential therapy target[J]. Aging Pathobiol Therap. 2020;2(1):32–7.CrossRef
16.
Madeline G, Roman LCF, Cunningham Geneva M, Cheng Christie, Allen Colton, Bai Yidong, Hubbard Gene B, Ikeno Yuji. Thioredoxin down-regulation in the cytosol in thioredoxin 2 transgenic mice did not have beneficial effects to extend lifespan in male C57BL/6 mice. Aging Pathobiol Ther. 2020;2(4):203–9.CrossRef
17.
Chaudhary P, Babu GS, Sobti RC, Gupta SK. HGF regulate HTR-8/SVneo trophoblastic cells migration/invasion under hypoxic conditions through increased HIF-1α expression via MAPK and PI3K pathways. J Cell Commun Signal. 2019;13(4):503–21.CrossRefPubMedPubMedCentral
18.
Dierks D, Garcia-Campos MA, Uzonyi A, Safra M, Edelheit S, Rossi A, Sideri T, Varier RA, Brandis A, Stelzer Y, et al. Multiplexed profiling facilitates robust m6A quantification at site, gene and sample resolution. Nat Methods. 2021;18(9):1060–7.CrossRefPubMed
19.
Nickel K, Zhu L, Mangalindan R, Snyder JM, Tucker M, Whitson J, Sweetwyne M, Valencia AP, Klug J, Jiang Z, Marcinek DJ, Rabinovitch P, Ladiges EW. Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice. Aging Pathobiol Ther, 2022;4(3):76–83.CrossRefPubMedPubMedCentral
20.
Li N, Huang L, Li Y, Chen X, Yang Y, Hou Y, Qiao C. Lin28B/miR-92b promote the proliferation, migration, and invasion in the pathogenesis of preeclampsia via the DKK1/Wnt/β-catenin pathway. Reprod Sci. 2020;27(3):815–22.CrossRefPubMed
21.
Uzan J, Carbonnel M, Piconne O, Asmar R, Ayoubi JM. Pre-eclampsia: pathophysiology, diagnosis, and management. Vasc Health Risk Manag. 2011;7:467–74.PubMedPubMedCentral
22.
Diniz ALD, Paes M, Diniz AD. Analyzing preeclampsia as the tip of the iceberg represented by women with long-term cardiovascular disease, atherosclerosis, and inflammation. Curr Atheroscler Rep. 2020;22(3):13.CrossRefPubMed
23.
Briceño-Pérez C, Briceño-Sanabria L, Vigil-De Gracia P. Prediction and prevention of preeclampsia. Hypertens Pregnancy. 2009;28(2):138–55.CrossRefPubMed
24.
25.
Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet. 2016;387(10022):999–1011.CrossRefPubMed
26.
Williamson RD, O’Keeffe GW, Kenny LC. Activin signalling and pre-eclampsia: from genetic risk to pre-symptomatic biomarker. Cytokine. 2015;71(2):360–5.CrossRefPubMed
27.
Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of preeclampsia. Curr Opin Nephrol Hypertens. 2015;24(2):131–8.CrossRefPubMed
28.
Mao M, Cheng Y, Yang J, Chen Y, Xu L, Zhang X, Li Z, Chen C, Ju S, Zhou J, et al. Multifaced roles of PLAC8 in cancer. Biomarker research. 2021;9(1):73.CrossRefPubMedPubMedCentral
29.
Li M, Liu D, Wang L, Wang W, Wang A, Yao Y. Expression of placenta-specific 8 in human oocytes, embryos, and models of in vitro implantation. Fertil Steril. 2016;106(3):781-789.e782.CrossRefPubMed
30.
Feng X, Wei Z, Tao X, Du Y, Wu J, Yu Y, Yu H, Zhao H. PLAC8 promotes the autophagic activity and improves the growth priority of human trophoblast cells. FASEB J. 2021;35(3):e21351.CrossRefPubMed
31.
Tang Y, Liu H, Li H, Peng T, Gu W, Li X. Hypermethylation of the HLA-G promoter is associated with preeclampsia. Mol Hum Reprod. 2015;21(9):736–44.CrossRefPubMed
32.
Kulkarni A, Chavan-Gautam P, Mehendale S, Yadav H, Joshi S. Global DNA methylation patterns in placenta and its association with maternal hypertension in pre-eclampsia. DNA Cell Biol. 2011;30(2):79–84.CrossRefPubMed
33.
Ohgane J, Hattori N, Oda M, Tanaka S, Shiota K. Differentiation of trophoblast lineage is associated with DNA methylation and demethylation. Biochem Biophys Res Commun. 2002;290(2):701–6.CrossRefPubMed
34.
Gu Y, Chu X, Morgan JA, Lewis DF, Wang Y. Upregulation of METTL3 expression and m6A RNA methylation in placental trophoblasts in preeclampsia. Placenta. 2021;103:43–9.CrossRefPubMed
35.
Fan W, Zhou W, Yan Q, Peng Y, Wang H, Kong C, Zhang B, Yu B, Chen L, Xue P. Upregulation of METTL14 contributes to trophoblast dysfunction by elevating FOXO3a expression in an m(6)A-dependent manner. Placenta. 2022;124:18–27.CrossRefPubMed
36.
Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X, Semenza GL. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA. 2016;113(14):E2047-2056.CrossRefPubMedPubMedCentral
37.
Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, et al. m(6)A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591-606.e596.CrossRefPubMedPubMedCentral
38.
Zheng Q, Yang F, Gan H, Jin L. Hypoxia induced ALKBH5 prevents spontaneous abortion by mediating m(6)A-demethylation of SMAD1/5 mRNAs. Biochim Biophys Acta. 2022;1869(10):119316.CrossRef
39.
Kang J, Tang Q, He J, Li L, Yang N, Yu S, Wang M, Zhang Y, Lin J, Cui T, et al. RNAInter v4.0: RNA interactome repository with redefined confidence scoring system and improved accessibility. Nucleic Acids Res. 2022;50(1):D326-d332.CrossRefPubMed
40.
Zhou Y, Zeng P, Li YH, Zhang Z, Cui Q. SRAMP: prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features. Nucleic Acids Res. 2016;44(10):e91.CrossRefPubMedPubMedCentral
Metadata
Title
Low m6A modification-mediated upregulation of PLAC8 promotes trophoblast cell invasion and migration in preeclampsia
Authors
Yajuan Zhang
Xiaoguang Guo
Zhimin Chen
Ruixia Guo
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Pre-Eclampsia
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01442-7

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