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01-12-2021 | Pre-Eclampsia | Research article

Differential circular RNA expression profiles in umbilical cord blood exosomes from preeclampsia patients

Authors: Minkai Cao, Juan Wen, Chaozhi Bu, Chunyan Li, Yu Lin, Hong Zhang, Yanfang Gu, Zhonghua Shi, Yan Zhang, Wei Long, Le Zhang

Published in: BMC Pregnancy and Childbirth | Issue 1/2021

Abstract

Background

Exosomal circular RNAs (circRNAs) are emerging as important regulators of physiological development and disease pathogenesis. However, the roles of exosomal circRNAs from umbilical cord blood in preeclampsia (PE) occurrence remains poorly understood.

Methods

We used microarray technology to establish the differential circRNA expression profiles in umbilical cord blood exosomes from PE patients compared with normal controls. Bioinformatics analysis was conducted to further predict the potential effects of the differentially expressed circRNAs and their interactions with miRNAs.

Results

According to the microarray data, we identified 143 significantly up-regulated circRNAs and 161 significantly down-regulated circRNAs in umbilical cord blood exosomes of PE patients compared with controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analyses showed that circRNA parental genes involved in the regulation of metabolic process, trophoblast growth and invasion were significantly enriched, which play important roles in PE development. Moreover, pathway network was constructed to reveal the key pathways in PE, such as PI3K-Akt signaling pathway. Further circRNA/miRNA interactions analysis demonstrated that most exosomal circRNAs had miRNA binding sites, and some miRNAs were associated with PE.

Conclusions

Our results highlight the importance of exosomal circRNAs in the pathogenesis of PE and lay a foundation for extensive studies on the role of exosomal circRNAs in PE development.

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Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet. 2016;387(10022):999–1011. https://doi.org/10.1016/S0140-6736(15)00070-7.CrossRefPubMed

Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308(5728):1592–4. https://doi.org/10.1126/science.1111726.CrossRefPubMed

American College of O, Gynecologists, Task Force on Hypertension in P. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013;122(5):1122–31.CrossRef

Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis. Bmj. 2013;347(nov07 15):f6564. https://doi.org/10.1136/bmj.f6564.CrossRefPubMedPubMedCentral

Valdiviezo C, Garovic VD, Ouyang P. Preeclampsia and hypertensive disease in pregnancy: their contributions to cardiovascular risk. Clin Cardiol. 2012;35(3):160–5. https://doi.org/10.1002/clc.21965.CrossRefPubMedPubMedCentral

Bokslag A, van Weissenbruch M, Mol BW, de Groot CJ. Preeclampsia; short and long-term consequences for mother and neonate. Early Hum Dev. 2016;102:47–50. https://doi.org/10.1016/j.earlhumdev.2016.09.007.CrossRefPubMed

Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy Y, et al. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics. 2012;129(6):e1552–61. https://doi.org/10.1542/peds.2011-3093.CrossRefPubMed

Hessvik NP, Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol Life Sci. 2018;75(2):193–208. https://doi.org/10.1007/s00018-017-2595-9.CrossRefPubMed

Gurunathan S, Kang MH, Jeyaraj M, Qasim M, Kim JH. Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes. Cells. 2019;8(4):307. https://doi.org/10.3390/cells8040307.

10.

Pillay P, Moodley K, Moodley J, Mackraj I. Placenta-derived exosomes: potential biomarkers of preeclampsia. Int J Nanomedicine. 2017;12:8009–23. https://doi.org/10.2147/IJN.S142732.CrossRefPubMedPubMedCentral

11.

Jayabalan N, Lai A, Ormazabal V, Adam S, Guanzon D, Palma C, et al. Adipose tissue Exosomal proteomic profile reveals a role on placenta glucose metabolism in gestational diabetes mellitus. J Clin Endocrinol Metab. 2019;104(5):1735–52. https://doi.org/10.1210/jc.2018-01599.CrossRefPubMed

12.

Salomon C, Scholz-Romero K, Sarker S, Sweeney E, Kobayashi M, Correa P, et al. Gestational diabetes mellitus is associated with changes in the concentration and bioactivity of placenta-derived Exosomes in maternal circulation across gestation. Diabetes. 2016;65(3):598–609. https://doi.org/10.2337/db15-0966.CrossRefPubMed

13.

Mitchell MD, Peiris HN, Kobayashi M, Koh YQ, Duncombe G, Illanes SE, et al. Placental exosomes in normal and complicated pregnancy. Am J Obstet Gynecol. 2015;213(4 Suppl):S173–81. https://doi.org/10.1016/j.ajog.2015.07.001.CrossRefPubMed

14.

Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25(8):981–4. https://doi.org/10.1038/cr.2015.82.CrossRefPubMedPubMedCentral

15.

Wang Y, Liu J, Ma J, Sun T, Zhou Q, Wang W, et al. Exosomal circRNAs: biogenesis, effect and application in human diseases. Mol Cancer. 2019;18(1):116. https://doi.org/10.1186/s12943-019-1041-z.CrossRefPubMedPubMedCentral

16.

Dai X, Chen C, Yang Q, Xue J, Chen X, Sun B, et al. Exosomal circRNA_100284 from arsenite-transformed cells, via microRNA-217 regulation of EZH2, is involved in the malignant transformation of human hepatic cells by accelerating the cell cycle and promoting cell proliferation. Cell Death Dis. 2018;9(5):454. https://doi.org/10.1038/s41419-018-0485-1.CrossRefPubMedPubMedCentral

17.

Li J, Li Z, Jiang P, Peng M, Zhang X, Chen K, et al. Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res. 2018;37(1):177. https://doi.org/10.1186/s13046-018-0822-3.CrossRefPubMedPubMedCentral

18.

Csorba R, Yilmaz A, Tsikouras P, Wieg C, Teichmann A, von Tempelhoff GF. Rheological parameters in the umbilical cord blood in moderate and severe forms of preeclampsia. Clin Hemorheol Microcirc. 2013;55(4):391–401. https://doi.org/10.3233/CH-131776.CrossRefPubMed

19.

Kwon JY, Maeng YS, Kwon YG, Kim YH, Kang MH, Park YW. Decreased endothelial progenitor cells in umbilical cord blood in severe preeclampsia. Gynecol Obstet Investig. 2007;64(2):103–8. https://doi.org/10.1159/000100081.CrossRef

20.

Yusuf K, Kamaluddeen M, Hasan SU, Al-Awad E, Finch RA, Akierman AR. Ionized calcium levels in umbilical cord blood of women with preeclampsia and normotensive pregnancies. J Maternal-fetal Neonat Med. 2012;25(2):203–5. https://doi.org/10.3109/14767058.2011.561895.CrossRef

21.

Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495(7441):384–8. https://doi.org/10.1038/nature11993.CrossRefPubMed

22.

Shao T, Pan YH, Xiong XD. Circular RNA: an important player with multiple facets to regulate its parental gene expression. Mol Ther Nucleic Acids. 2021;23:369–76. https://doi.org/10.1016/j.omtn.2020.11.008.CrossRefPubMed

23.

Bieche I, Parfait B, Nogues C, Andrieu C, Vidaud D, Spyratos F, et al. The CGA gene as new predictor of the response to endocrine therapy in ER alpha-positive postmenopausal breast cancer patients. Oncogene. 2001;20(47):6955–9. https://doi.org/10.1038/sj.onc.1204739.CrossRefPubMed

24.

Moodley D, Moodley J, Buck R, Haneef R, Payne A. Free alpha-subunits of human chorionic gonadotropin in preeclampsia. Int J Gynaecol Obstet. 1995;49(3):283–7. https://doi.org/10.1016/0020-7292(95)02375-M.CrossRefPubMed

25.

Liu J, Song G, Meng T, Zhao G. Identification of differentially expressed genes and signaling pathways in placenta tissue of early-onset and late-onset pre-Eclamptic pregnancies by integrated bioinformatics analysis. Med Sci Monitor. 2020;26:e921997.

26.

Varkonyi T, Nagy B, Fule T, Tarca AL, Karaszi K, Schonleber J, Hupuczi P, Mihalik N, Kovalszky I, Rigo J, Jr. et al: Microarray profiling reveals that placental transcriptomes of early-onset HELLP syndrome and preeclampsia are similar. Placenta 2011, 32 Suppl:S21–S29, DOI: https://doi.org/10.1016/j.placenta.2010.04.014.

27.

Bieche I, Parfait B, Le Doussal V, Olivi M, Rio MC, Lidereau R, et al. Identification of CGA as a novel estrogen receptor-responsive gene in breast cancer: an outstanding candidate marker to predict the response to endocrine therapy. Cancer Res. 2001;61(4):1652–8.PubMed

28.

Zhu L, Plow EF, Qin J. Initiation of focal adhesion assembly by Talin and kindlin: a dynamic view. Protein Sci. 2020.

29.

Ilic D, Genbacev O, Jin F, Caceres E, Almeida EA, Bellingard-Dubouchaud V, et al. Plasma membrane-associated pY397FAK is a marker of cytotrophoblast invasion in vivo and in vitro. Am J Pathol. 2001;159(1):93–108. https://doi.org/10.1016/S0002-9440(10)61677-X.CrossRefPubMedPubMedCentral

30.

von Versen-Hoeynck FM, Powers RW. Maternal-fetal metabolism in normal pregnancy and preeclampsia. Front Biosci. 2007;12(1):2457–70. https://doi.org/10.2741/2247.CrossRef

31.

Fragkiadaki P, Soulitzis N, Sifakis S, Koutroulakis D, Gourvas V, Vrachnis N, et al. Downregulation of notch signaling pathway in late preterm and term placentas from pregnancies complicated by preeclampsia. PLoS One. 2015;10(5):e0126163. https://doi.org/10.1371/journal.pone.0126163.CrossRefPubMedPubMedCentral

32.

Zhu X, Cao Q, Li X, Wang Z. Knockdown of TACC3 inhibits trophoblast cell migration and invasion through the PI3K/Akt signaling pathway. Mol Med Rep. 2016;14(4):3437–42. https://doi.org/10.3892/mmr.2016.5659.CrossRefPubMed

33.

Li Z, Yanfang W, Li J, Jiang P, Peng T, Chen K, et al. Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR-338/MACC1/MET pathway in pancreatic cancer. Cancer Lett. 2018;432:237–50. https://doi.org/10.1016/j.canlet.2018.04.035.CrossRefPubMed

34.

Zhang H, Zhu L, Bai M, Liu Y, Zhan Y, Deng T, et al. Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway. Int J Cancer. 2019;144(10):2501–15. https://doi.org/10.1002/ijc.31977.CrossRefPubMed

35.

Xue J, Liu Y, Luo F, Lu X, Xu H, Liu X, et al. Circ100284, via miR-217 regulation of EZH2, is involved in the arsenite-accelerated cell cycle of human keratinocytes in carcinogenesis. Biochim Biophys Acta Mol Basis Dis. 2017;1863(3):753–63. https://doi.org/10.1016/j.bbadis.2016.12.018.CrossRefPubMed

36.

Han L, Luo QQ, Peng MG, Zhang Y, Zhu XH. miR-483 is downregulated in pre-eclampsia via targeting insulin-like growth factor 1 (IGF1) and regulates the PI3K/Akt/mTOR pathway of endothelial progenitor cells. J Obstet Gynaecol Res. 2021;47(1):63–72. https://doi.org/10.1111/jog.14412.CrossRefPubMed

37.

Tang Q, Gui J, Wu X, Wu W. Downregulation of miR-424 in placenta is associated with severe preeclampsia. Pregnancy Hyperten. 2019;17:109–12. https://doi.org/10.1016/j.preghy.2019.05.017.CrossRef

38.

Yang X, Meng T. MicroRNA-431 affects trophoblast migration and invasion by targeting ZEB1 in preeclampsia. Gene. 2019;683:225–32. https://doi.org/10.1016/j.gene.2018.10.015.CrossRefPubMed

39.

Xu P, Zhao Y, Liu M, Wang Y, Wang H, Li YX, et al. Variations of microRNAs in human placentas and plasma from preeclamptic pregnancy. Hypertension. 2014;63(6):1276–84. https://doi.org/10.1161/HYPERTENSIONAHA.113.02647.CrossRefPubMed

40.

Choi SY, Yun J, Lee OJ, Han HS, Yeo MK, Lee MA, et al. MicroRNA expression profiles in placenta with severe preeclampsia using a PNA-based microarray. Placenta. 2013;34(9):799–804. https://doi.org/10.1016/j.placenta.2013.06.006.CrossRefPubMed

41.

Salomon C, Guanzon D, Scholz-Romero K, Longo S, Correa P, Illanes SE, et al. Placental Exosomes as early biomarker of preeclampsia: potential role of Exosomal MicroRNAs across gestation. J Clin Endocrinol Metab. 2017;102(9):3182–94. https://doi.org/10.1210/jc.2017-00672.CrossRefPubMed

42.

Sandrim VC, Luizon MR, Palei AC, Tanus-Santos JE, Cavalli RC. Circulating microRNA expression profiles in pre-eclampsia: evidence of increased miR-885-5p levels. BJOG. 2016;123(13):2120–8. https://doi.org/10.1111/1471-0528.13903.CrossRefPubMed

Title: Differential circular RNA expression profiles in umbilical cord blood exosomes from preeclampsia patients
Authors: Minkai Cao
Juan Wen
Chaozhi Bu
Chunyan Li
Yu Lin
Hong Zhang
Yanfang Gu
Zhonghua Shi
Yan Zhang
Wei Long
Le Zhang
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Pre-Eclampsia
Published in: BMC Pregnancy and Childbirth / Issue 1/2021
Electronic ISSN: 1471-2393
DOI: https://doi.org/10.1186/s12884-021-03777-7

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Springer Medicine

Differential circular RNA expression profiles in umbilical cord blood exosomes from preeclampsia patients

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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