Elevated levels of hypoxia‐inducible microRNA‐210 in pre‐eclampsia: new insights into molecular mechanisms for the disease
Open accessAbstract
Pre‐eclampsia is a leading cause of maternal and foetal morbidity and mortality worldwide. Insufficient uteroplacental oxygenation is believed to be responsible for the disease. However, what molecular events involve in hypoxic responses and how they affect placental development remain unclear. Recently, miRNAs have emerged as a new class of molecules in response to hypoxia. We show here that the expression of microRNA‐210 (mir‐210) is up‐regulated in patients with pre‐eclampsia, as well as in trophoblast cells cultured under hypoxic conditions. Ectopic expression of mir‐210 inhibited the migration and invasion capability of trophoblast cells. Ephrin‐A3 and Homeobox‐A9, which related with cell migration and vascular remodelling, were then experimentally validated as the functional targets of mir‐210 both in vivo and in vitro. Using luciferase reporter, chromatin immunoprecipitation (ChIP) and small interfering RNA (siRNA) experiments, we finally identified a new transcriptional mechanism that the overexpression of mir‐210 under hypoxia was regulated by NF‐κB transcriptional factor p50, apart from the well‐known HIF 1α. Taken together, our study implicates an important role for mir‐210 in the molecular mechanism of pre‐eclampsia.
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Other targets identified for miR-210 include the steroidogenic enzyme hydroxysteroid (17-ß) dehydrogenase 1, ephrin-A3 and homeobox-A9 which are involved in trophoblast cell migration and vascular remodeling, and thrombospondin type 1 domain containing 7A in the placental vasculature.
“Besides mitochondria, other targets identified for miR-210 include the steroidogenic enzyme hydroxysteroid (17-ß) dehydrogenase 1 (272), ephrin-A3 and homeobox-A9 which are involved in trophoblast cell migration and vascular remodeling (611), and thrombospondin type 1 domain containing 7A in the placental vasculature (351).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [611]
MiR-210 is increased in normal placentas from pregnancies at high altitude, and in placentas from pregnancies complicated by pre-eclampsia.
“It is increased in normal placentas from pregnancies at high altitude (121), and in placentas from pregnancies complicated by pre-eclampsia (272, 351, 401, 611).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [611]
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Cites
Bartel (2004) · doi:10.1016/s0092-8674(04)00045-5 · Cited by 34,714 · see citing works
Real-time quantification of microRNAs by stem-loop RT-PCR
Chen, C. (2005) · Nucleic Acids Research · doi:10.1093/nar/gni178 · Cited by 4,931 · see citing works
NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., Johnson, R. S., Haddad, G. G., & Karin, M. (2008) · Nature · doi:10.1038/nature06905 · Cited by 1,614 · see citing works
Ribo-gnome: The Big World of Small RNAs
Zamore, P. D., & Haley, B. (2005) · Science · doi:10.1126/science.1111444 · Cited by 1,288 · see citing works
A MicroRNA Signature of Hypoxia
Kulshreshtha, R., Ferracin, M., Wojcik, S. E., Garzon, R., Alder, H., Agosto-Perez, F. J., Davuluri, R., Liu, C.-G., Croce, C. M., Negrini, M., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01395-06 · Cited by 1,055 · see citing works
Phylogenetic Shadowing and Computational Identification of Human microRNA Genes
Berezikov, E., Guryev, V., van de Belt, J., Wienholds, E., Plasterk, R. H. A., & Cuppen, E. (2005) · Cell · doi:10.1016/j.cell.2004.12.031 · Cited by 1,008 · see citing works
Ng, E. K. O., Chong, W. W. S., Jin, H., Lam, E. K. Y., Shin, V. Y., Yu, J., Poon, T. C. W., Ng, S. S. M., & Sung, J. J. Y. (2009) · Gut · doi:10.1136/gut.2008.167817 · Cited by 936 · see citing works
Regulation of Human Placental Development by Oxygen Tension
Genbačev, O., Zhou, Y., Ludlow, J. W., & Fisher, S. J. (1997) · Science · doi:10.1126/science.277.5332.1669 · Cited by 914 · see citing works
Fasanaro, P., D'Alessandra, Y., Di Stefano, V., Melchionna, R., Romani, S., Pompilio, G., Capogrossi, M. C., & Martelli, F. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800731200 · Cited by 912 · see citing works
Detection and Characterization of Placental MicroRNAs in Maternal Plasma
Chim, S. S. C., Shing, T. K. F., Hung, E. C. W., Leung, T.-Y., Lau, T. K., Chiu, R. W. K., & Lo, Y. M. D. (2008) · Clinical Chemistry · doi:10.1373/clinchem.2007.097972 · Cited by 844 · see citing works
Cummins, E. P., Berra, E., Comerford, K. M., Ginouves, A., Fitzgerald, K. T., Seeballuck, F., Godson, C., Nielsen, J. E., Moynagh, P., Pouyssegur, J., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602235103 · Cited by 788 · see citing works
Regulation of hypoxia-inducible factor-1α by NF-κB
van Uden, P., Kenneth, N. S., & Rocha, S. (2008) · Biochemical Journal · doi:10.1042/bj20080476 · Cited by 729 · see citing works
hsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer
Camps, C., Buffa, F. M., Colella, S., Moore, J., Sotiriou, C. P., Sheldon, H., Harris, A. L., Gleadle, J., & Ragoussis, J. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1755 · Cited by 658 · see citing works
Caniggia, I., Mostachfi, H., Winter, J., Gassmann, M., Lye, S. J., Kuliszewski, M., & Post, M. (2000) · Journal of Clinical Investigation · doi:10.1172/jci8316 · Cited by 644 · see citing works
Hypoxia-Inducible mir-210 Regulates Normoxic Gene Expression Involved in Tumor Initiation
Huang, X., Ding, L., Bennewith, K. L., Tong, R. T., Welford, S. M., Ang, K. K., Story, M. D., Le, Q., & Giaccia, A. J. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.006 · Cited by 616 · see citing works
Hypoxia-responsive transcription factors
Cummins, E. P., & Taylor, C. T. (2005) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-005-1413-7 · Cited by 462 · see citing works
Pineles, B. L., Romero, R., Montenegro, D., Tarca, A. L., Han, Y. M., Kim, Y. M., Draghici, S., Espinoza, J., Kusanovic, J. P., Mittal, P., et al. (2007) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2007.01.008 · Cited by 450 · see citing works
MicroRNA regulation of DNA repair gene expression in hypoxic stress
Crosby, M. E., Kulshreshtha, R., Ivan, M., & Glazer, P. M. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2516 · Cited by 437 · see citing works
BelAiba, R. S., Bonello, S., Zähringer, C., Schmidt, S., Hess, J., Kietzmann, T., & Görlach, A. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-04-0391 · Cited by 423 · see citing works
Molecular Evidence of Placental Hypoxia in Preeclampsia
Soleymanlou, N., Jurišica, I., Nevo, O., Ietta, F., Zhang, X., Zamudio, S., Post, M., & Caniggia, I. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0078 · Cited by 394 · see citing works
MiR-210 – micromanager of the hypoxia pathway
Huang, X., Le, Q., & Giaccia, A. J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.004 · Cited by 376 · see citing works
Zhu, X.-M., Han, T., Sargent, I. L., Yin, G.-W., & Yao, Y.-Q. (2009) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2008.12.045 · Cited by 345 · see citing works
miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer
Giannakakis, A., Sandaltzopoulos, R., Greshock, J. D., Liang, S., Huang, J., Hasegawa, K., Li, C., O’Brien-Jenkins, A., Katsaros, D., Weber, B. L., et al. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.2.5297 · Cited by 341 · see citing works
MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT
Zhang, Z., Sun, H., Dai, H. A., Walsh, R., Imakura, M., Schelter, J. M., Burchard, J., Dai, X., Chang, A. N., Diaz, R. L., et al. (2009) · Cell Cycle · doi:10.4161/cc.8.17.9387 · Cited by 284 · see citing works
Regulation of trophoblast invasion: from normal implantation to pre-eclampsia
Goldman‐Wohl, D., & Yagel, S. (2002) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(01)00687-6 · Cited by 279 · see citing works
Rajakumar, A., Brandon, H. M., Daftary, A., Ness, R., & Conrad, K. P. (2004) · Placenta · doi:10.1016/j.placenta.2004.02.011 · Cited by 251 · see citing works
Working Group Report on High Blood Pressure in Pregnancy
Moser, M. (2001) · Journal of Clinical Hypertension · doi:10.1111/j.1524-6175.2001.00458.x · Cited by 248 · see citing works
Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models
Khalil, R. A., & Granger, J. P. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00762.2001 · Cited by 233 · see citing works
Normal nonmetastatic human trophoblast cells share in vitro invasive properties of malignant cells
Yagel, S., Parhar, R. S., Jeffrey, J. J., et al. (1988) · Journal of Cellular Physiology · doi:10.1002/jcp.1041360309 · Cited by 198 · see citing works
Prenatal diagnosis: progress through plasma nucleic acids
Lo, Y. M. D., & Chiu, R. W. K. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1982 · Cited by 197 · see citing works
Marinescu, V. D., Kohane, I. S., & Riva, A. (2005) · BMC Bioinformatics · doi:10.1186/1471-2105-6-79 · Cited by 194 · see citing works
Hypoxia induces microRNA miR‐210 in vitro and in vivo
Pulkkinen, K. H., Malm, T., Turunen, M. P., Koıstınaho, J., & Ylä‐Herttuala, S. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.05.048 · Cited by 188 · see citing works
Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension
McParland, P., Pearce, J. M., & Chamberlain, G. V. P. (1990) · The Lancet · doi:10.1016/0140-6736(90)91377-m · Cited by 186 · see citing works
Cindrová‐Davies, T. (2009) · Placenta · doi:10.1016/j.placenta.2008.11.020 · Cited by 145 · see citing works
Zhang, J., & Hughes, S. (2006) · The Journal of Pathology · doi:10.1002/path.1937 · Cited by 135 · see citing works
Brühl, T., Urbich, C., Aicher, D., Acker‐Palmer, A., Zeiher, A. M., & Dimmeler, S. (2004) · Circulation Research · doi:10.1161/01.res.0000120861.27064.09 · Cited by 131 · see citing works
Savvidou, M. D., Yu, C.-S., Harland, L. C., Hingorani, A. D., & Nicolaides, K. H. (2006) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2006.03.065 · Cited by 97 · see citing works
Shah, T. J., & Walsh, S. W. (2007) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2006.08.038 · Cited by 97 · see citing works
Preeclampsia Activates Circulating Immune Cells with Engagement of the NF‐κB Pathway
Luppi, P., Tse, H. M., Lain, K. Y., Markovic, N., Piganelli, J. D., & DeLoia, J. A. (2006) · American Journal of Reproductive Immunology · doi:10.1111/j.1600-0897.2006.00386.x · Cited by 87 · see citing works
Uteroplacental Blood Flow in Pregnancy Induced Hypertension
Lunell, N. O., Lewander, R., Mamoun, I., Nylund, L., Sarby, S., & Thornström, S. (1984) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365518409085374 · Cited by 68 · see citing works
Prediction of Preeclampsia – A Workshop Report
Than, N. G., Romero, R. J., Hillermann, R., Cozzi, V., Nie, G., & Huppertz, B. (2007) · Placenta · doi:10.1016/j.placenta.2007.10.008 · Cited by 66 · see citing works
Chan, K. C. A., & Lo, Y. M. D. (2007) · British Journal of Cancer · doi:10.1038/sj.bjc.6603625 · Cited by 60 · see citing works
8-Iso-Prostaglandin F 2α Reduces Trophoblast Invasion and Matrix Metalloproteinase Activity
Staff, A. C., Ranheim, T., Henriksen, T., & Halvorsen, B. L. (2000) · Hypertension · doi:10.1161/01.hyp.35.6.1307 · Cited by 58 · see citing works
Ajayi, F. A., Kongoasa, N., Gaffey, T. A., Asmann, Y. W., Watson, W. J., Baldi, A., Lala, P. K., Shridhar, V., Brost, B. C., & CHIEN, J. R. (2008) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2008.04.046 · Cited by 53 · see citing works
Trophoblast biology, responses to hypoxia and placental dysfunction in preeclampsia
Rampersad, R. M. (2006) · Frontiers in bioscience · doi:10.2741/2246 · Cited by 47 · see citing works
Nagamatsu, T., Fujii, T., Ishikawa, T., et al. (2003) · Placenta · doi:10.1016/j.placenta.2003.08.015 · Cited by 44 · see citing works
Eph and ephrin expression in normal placental development and preeclampsia
Goldman‐Wohl, D., Greenfield, C., Haimov‐Kochman, R., et al. (2004) · Placenta · doi:10.1016/j.placenta.2004.01.016 · Cited by 40 · see citing works
Seeho, S. K. M., Park, J. H., Rowe, J., Morris, J. M., & Gallery, E. D. M. (2008) · Human Reproduction · doi:10.1093/humrep/den066 · Cited by 34 · see citing works
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Muralimanoharan, S., Maloyan, A., Mele, J., Guo, C., Myatt, L. G., & Myatt, L. (2012) · Placenta · doi:10.1016/j.placenta.2012.07.002 · Cited by 237 · see citing works
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- Authors
- Zhang, Y., Fei, M., Xue, G., Zhou, Q., Jia, Y., Li, L., Xin, H., & Sun, S.
- Affiliations
- Second Military Medical University (CN)
- First Affiliated Hospital of Anhui Medical University (CN)
- Second Hospital of Hebei Medical University (CN)
- Corresponding author
- Sun, Shuhan
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2012-01-27
- Volume
- 16
- Issue
- 2
- Pages
- 249-259
- ISSN
- 1582-1838 (ISSN-L)
- 1582-4934
- PMC
- PMC3823289
- OpenAlex
- W2037820964
- Cited by
- 236
- References
- 48
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 18 · 2023: 13 · 2022: 11 · 2021: 18 · 2020: 21 · 2019: 20 · 2018: 21 · 2017: 17 · 2016: 22 · 2015: 19 · 2014: 14 · 2013: 19 · 2012: 10
- FWCI
- 18.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
- Keywords
- preeclampsia, miR-210, hypoxia, trophoblast, ephrin-A3, cell migration, cell invasion, NF-κB p50, HIF-1α, placental development, vascular remodeling
- MeSH terms
- Hypoxia, Cell Movement, Female, Humans, Pre-Eclampsia, Pregnancy, Pregnancy Complications, Trophoblasts, Case-Control Studies, Homeodomain Proteins, RNA Interference, RNA, Small Interfering, MicroRNAs, Ephrin-A3, Cell Line, Tumor, Hypoxia-Inducible Factor 1, alpha Subunit, NF-kappa B p50 Subunit
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