The role of E2F8 in the human placenta
Open accessAbstract
Recent studies have reported that E2F transcription factor (E2F) 8, an atypical E2F transcription factor, serves a critical role in promoting the growth and development of the murine placenta. However, the function of E2F8 in the human placenta remains unknown. Invasion of extravillous trophoblasts (EVTs) into the maternal decidua is known to be important for the development of the human placenta. To investigate the role of E2F8 in human placental development, E2F8 localisation was examined in the human placenta and E2F8 mRNA expression was detected in primary cultured EVTs. The human EVT cell line, HTR‑8/SVneo, was divided into two groups and treated separately, one with retrovirus expressing short hairpin (sh)‑RNA against E2F8 (shE2F8 cells) and the other with non‑target control shRNA (shControl cells). The cell functions, including cell cycle, proliferation, invasion and adhesion, were compared between the shE2F8 and shControl cells. A histological examination revealed that E2F8 was localised in the decidua cells, EVTs, and cytotrophoblasts in the placenta. E2F8 mRNA was confirmed to be expressed in cultured primary EVTs. No significant difference was observed in the cell cycle, proliferation or adhesion between the shE2F8 and shControl cells. The invasive ability was ~2‑fold higher in the shE2F8 cells when compared with the shControl cells (P<0.01). Production of matrix metalloproteinase‑1 was significantly increased in the shE2F8 cells when compared with the shControl cells (P<0.05). Taken together, E2F8 is present in the EVTs of the human placenta, but, unlike murine placenta, it may suppress the invasiveness of EVTs. E2F8 was also present in cytotrophoblasts in cell columns, which have no invasive ability and differentiate into EVTs. In conclusion, E2F8 also exists in the human placenta, and its function may be different from that in the murine placenta, although further investigation is required.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
E2f7 and E2f8 are expressed in several other tissues, such as placenta and pancreas, where they are implicated in arresting the cell cycle.
“These mitotic inhibitors are expressed in several other tissues, such as the placenta and pancreas, where they are also implicated in arresting the cell cycle (8, 47–49).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [49]
The Results (page unavailable) show E2F8 expression in the human placenta, but the study did not investigate E2F7 expression there or address expression in the pancreas. Its Results also report that E2F8 silencing did not significantly affect the cell cycle or proliferation in the placental cell line tested, so this paper does not support the attributed role in cell-cycle arrest. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Placental development: Lessons from mouse mutants
Rossant, J., & Cross, J. C. (2001) · Nature Reviews Genetics · doi:10.1038/35080570 · Cited by 1,273 · cited 3× · see citing works
“Labyrinth trophoblasts are analogous in function to syncytiotrophoblasts (7).”
BackgroundEstablishment and Characterization of First Trimester Human Trophoblast Cells with Extended Lifespan
Graham, C. H., Hawley, T. S., Hawley, R. G., MacDougall, J. R., Kerbel, R. S., Khoo, N. K. S., & Lala, P. K. (1993) · Experimental Cell Research · doi:10.1006/excr.1993.1139 · Cited by 1,056 · cited 1× · see citing works
“The establishment of the human EVT cell line HTR-8/SVneo has been reported previously (10).”
BackgroundFetal growth restriction: current knowledge
Nardozza, L. M. M., Caetano, A. C. R., Zamarian, A. C. P., Mazzola, J. B., Silva, C. P., Marçal, V. M. G., Lobo, T. F., Peixoto, A. B., & Júnior, E. A. (2017) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-017-4341-9 · Cited by 631 · cited 1× · see citing works
“perinatal morbidity and mortality (1), but currently there is no clinically effective treatment.”
BackgroundThe E2F1–3 transcription factors are essential for cellular proliferation
Wu, L., Timmers, C. D., Maiti, B., Saavedra, H. I., Sang, L., Chong, G. T., Nuckolls, F., Giangrande, P. H., Wright, F. A., Field, S. J., et al. (2001) · Nature · doi:10.1038/35106593 · Cited by 620 · cited 1× · see citing works
“E2F1 and E2F3 are known to be essential for cellular proliferation as classical E2F proteins (21), but E2F8 functionally antagonises the classical E2F proteins.”
BackgroundOnly humans have human placentas: molecular differences between mice and humans
Schmidt, A., Prieto, D. M. M., Pastuschek, J., Fröhlich, K., & Markert, U. R. (2015) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2015.03.001 · Cited by 226 · see citing works
Kajiyama, H., Shibata, K., Terauchi, M., Ino, K., Nawa, A., & Kikkawa, F. (2007) · International Journal of Cancer · doi:10.1002/ijc.23083 · Cited by 220 · see citing works
Self-citationMaiti, B., Li, J., de Bruin, A., Gordon, F., Timmers, C. D., Opavský, R., Patil, K., Tuttle, J., Cleghorn, W. M., & Leone, G. W. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501410200 · Cited by 189 · cited 1× · see citing works
“Additionally, in this study, the role of E2F7 was not investigated, but E2F7 has been reported to be have a synergistic function with E2F8 (29,30).”
BackgroundTrophoblast invasion: Assessment of cellular models using gene expression signatures
Bilban, M., Tauber, S., Haslinger, P., Pollheimer, J., Saleh, L., Pehamberger, H., Wagner, O. F., & Knöfler, M. (2010) · Placenta · doi:10.1016/j.placenta.2010.08.011 · Cited by 183 · see citing works
Weijts, B. G. M. W., Bakker, W. J., Cornelissen, P. W. A., Liang, K.-H., Schaftenaar, F. H., Westendorp, B., de Wolf, C. A. C. M. T., Paciejewska, M., Scheele, C. L. G. J., Kent, L. N., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.231 · Cited by 128 · cited 2× · see citing works
“Members of the E2F family are transcriptional factors controlling cell cycle, although E2F7 and E2F8 have recently been identified as atypical E2F family members (3).”
BackgroundAtypical E2F Repressors and Activators Coordinate Placental Development
Ouseph, M. M., Li, J., Chen, H., Pécot, T., Wenzel, P. L., Thompson, J. C., Comstock, G., Chokshi, V., Byrne, M., Forde, B., et al. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.01.013 · Cited by 104 · cited 10× · see citing works
“However, the function of E2F8 in human EVTs does not seem to be consistent with that in murine TGCs.”
BackgroundResultInfluentialJohnson, J. L., Pillai, S., Pernazza, D., Sebti, S. M., Lawrence, N. J., & Chellappan, S. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-2647 · Cited by 94 · see citing works
E2f3a and E2f3b Contribute to the Control of Cell Proliferation and Mouse Development
Chong, J.-L., Tsai, S., Sharma, N., Opavský, R., Price, R., Wu, L., Fernández, S., & Leone, G. W. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01161-08 · Cited by 82 · cited 1× · see citing works
“On the other hand, in murine placenta E2F3 is thought to have a negative role in placental growth (20).”
BackgroundThe Rb–E2F Transcriptional Regulatory Pathway in Tumor Angiogenesis and Metastasis
Schaal, C. M., Pillai, S., & Chellappan, S. (2014) · Advances in cancer research · doi:10.1016/b978-0-12-800249-0.00004-4 · Cited by 78 · see citing works
Matsumoto, K., Miki, R., Nakayama, M., Tatsumi, N., & Yokouchi, Y. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.04.021 · Cited by 75 · cited 1× · see citing works
“) with Blend taq (Toyobo Life Science), as previously reported (12).”
MethodSelf-citationSynergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer
Thurlings, I., Martínez-López, L. M., Westendorp, B., Zijp, M., Kuiper, R., Tooten, P. C. J., Kent, L. N., Leone, G. W., Vos, H. R., Burgering, B. M. T., et al. (2016) · Oncogene · doi:10.1038/onc.2016.251 · Cited by 70 · cited 1× · see citing works
“Additionally, in this study, the role of E2F7 was not investigated, but E2F7 has been reported to be have a synergistic function with E2F8 (29,30).”
BackgroundStructural insights into the DNA-binding specificity of E2F family transcription factors
Morgunova, E. Y., Yin, Y., Jolma, A., Dave, K., Schmierer, B., Popov, A. N., Eremina, N., Nilsson, L., & Taipale, J. (2015) · Nature Communications · doi:10.1038/ncomms10050 · Cited by 68 · cited 1× · see citing works
“The E2F transcription family proteins have the consensus winged helix DNA-binding motif sequence (25).”
BackgroundmiR-141 Contributes to Fetal Growth Restriction by Regulating PLAG1 Expression
Tang, Q., Wu, W., Xu, X., Huang, L. H., Gao, Q., Chen, H., Sun, H., Xia, Y., Sha, J., Wang, X., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0058737 · Cited by 68 · cited 1× · see citing works
“A previous study reported that E2F3 expression in FGR placentas was lower than that in the placentas of normal control (18).”
BackgroundQi, Q.-R., Zhao, X.-Y., Zuo, R.-J., Wang, T.-S., Gu, X.-W., Liu, J.-L., & Yang, Z.-M. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1033593 · Cited by 58 · cited 1× · see citing works
“Additionally, E2F8 was detected in decidual cells, as previously reported (17).”
BackgroundLian, I. A., Toft, J. H., Olsen, G. D., Langaas, M., Bjørge, L., Eide, I. P., Børdahl, P. E., & Austgulen, R. (2010) · Placenta · doi:10.1016/j.placenta.2010.04.003 · Cited by 51 · cited 7× · see citing works
“MMP-1 was listed as one of upregulated proteins in shE2F8 cells (Fig.”
BackgroundInfluentialSuman, P., & Sk, G. (2012) · Placenta · doi:10.1016/j.placenta.2012.06.017 · Cited by 50 · cited 10× · see citing works
“To knockdown E2F8 expression, HTR-8/SVneo cells were infected with retrovirus expressing shRNA against E2F8 or non-target control shRNA.”
ResultInfluentialLiu, X., Wang, J., Gao, L., Liu, H., & Liu, C. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000484626 · Cited by 44 · cited 1× · see citing works
“2-fold change to identify differentially expressed proteins in shE2F8 cells compared to those in shControl cells, in accordance with a previous report (15,16).”
ResultThe Loss of Endoglin Promotes the Invasion of Extravillous Trophoblasts
Mano, Y., Kotani, T., Shibata, K., Matsumura, H., Tsuda, H., Sumigama, S., Yamamoto, E., Iwase, A., Senga, T., & Kikkawa, F. (2011) · Endocrinology · doi:10.1210/en.2011-1088 · Cited by 39 · cited 2× · see citing works
“Villous explant cultures were established as previously reported (8), with slight modifications.”
MethodSelf-citationYamamoto, E., Ino, K., Miyoshi, E., Inamori, K., Abe, A., Sumigama, S., Iwase, A., Kajiyama, H., Shibata, K., Nawa, A., et al. (2008) · Endocrinology · doi:10.1210/en.2008-1005 · Cited by 39 · cited 1× · see citing works
“A first trimester pregnant uterus was previously obtained from a patient who underwent a hysterectomy during pregnancy (8,9).”
MethodSelf-citationAtypical E2fs Control Lymphangiogenesis through Transcriptional Regulation of Ccbe1 and Flt4
Weijts, B., van Impel, A., Schulte-Merker, S., & de Bruin, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073693 · Cited by 37 · cited 1× · see citing works
“The functions of E2F7 and E2F8 have also been investigated, and they are reported to control angiogenesis (3-5).”
BackgroundHIF proteins connect the RB-E2F factors to angiogenesis
Bakker, W. J., Weijts, B. G. M. W., Westendorp, B., & de Bruin, A. (2013) · Transcription · doi:10.4161/trns.23680 · Cited by 21 · cited 1× · see citing works
“The functions of E2F7 and E2F8 have also been investigated, and they are reported to control angiogenesis (3-5).”
BackgroundNystad, M., Sitras, V., Larsen, M., & Acharya, G. (2014) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2014.06.047 · Cited by 15 · cited 10× · see citing works
“To knockdown E2F8 expression, HTR-8/SVneo cells were infected with retrovirus expressing shRNA against E2F8 or non-target control shRNA.”
ResultInfluentialTranscription factors E2F1 and E2F3 are expressed in placenta but do not regulate MMP14
Kaitu’u‐Lino, T. J., Hastie, R. M., Cannon, P., Nguyen, H., Lee, S., Hannan, N. J., & Tong, S. Y. C. (2015) · Placenta · doi:10.1016/j.placenta.2015.06.007 · Cited by 12 · cited 1× · see citing works
“Another research demonstrated that E2F1 was significantly downregulated in placenta with severe early-onset preeclampsia (19), which is known to be caused by failed EVT invasion.”
BackgroundSun, Y., Gao, C., Wang, X., Yuan, Y., Liu, Y., & Jia, J.-G. (2017) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2017.09.012 · Cited by 11 · cited 1× · see citing works
“2-fold change to identify differentially expressed proteins in shE2F8 cells compared to those in shControl cells, in accordance with a previous report (15,16).”
ResultAltered proteomic profile in umbilical arterial serum from mothers with schizophrenia
Moriyama, Y., Kotani, T., Ushida, T., Imai, K., Nakano, T., Tsuda, H., & Kikkawa, F. (2018) · Schizophrenia Research · doi:10.1016/j.schres.2018.02.024 · Cited by 10 · cited 1× · see citing works
“The procedure was performed in accordance with a previous report (14).”
MethodSelf-citation
Flagged first, then by citations
Cited by
Sorted by citations
Progress in deciphering trophoblast cell differentiation during human placentation
Xiao, Z., Long, Y., Liang, X., & Wang, H. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2020.08.010 · Cited by 88 · see citing works
Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade
Jin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., Peng, W. C., & Nusse, R. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203849119 · Cited by 26 · see citing works
Park, S.-A., Lim, Y.-J., Ku, W. L., Zhang, D., Cui, K., Tang, L.-Y., Chia, C., Zanvit, P., Chen, Z., Jin, W., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33733-8 · Cited by 22 · see citing works
Single-cell RNA sequencing identifies CXADR as a fate determinant of the placental exchange surface
Angelova, D. M., Tsolova, A. O., Prater, M., Ballasy, N., Bacon, W., Hamilton, R. S., Blackwell, D., Yu, Z., Li, X., Liu, X., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-55597-w · Cited by 9 · see citing works
“For instance, the E2f8 -directed regulon wasparticularly prevalent inthe LP SynT-II branch, which is consistent with the demonstrated importance of E2f7 / E2f8 in the placental labyrinth 56 – 58 .”
Interleukin-17A stimulation induces alterations in Microglial microRNA expression profiles
Iitani, Y., Miki, R., Imai, K., Fuma, K., Ushida, T., Tano, S., Yoshida, K., Yokoi, A., Kajiyama, H., & Kotani, T. (2023) · Pediatric Research · doi:10.1038/s41390-023-02825-6 · Cited by 9 · see citing works
Self-citationPrice, Z. K., Lokman, N. A., Sugiyama, M., Koya, Y., Yoshihara, M., Oehler, M. K., Kajiyama, H., & Ricciardelli, C. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04972-9 · Cited by 7 · see citing works
“Protein was extracted from duplicate samples for each treatment group as previously described and analysed using the Orbitrap Fusion (Thermo Fisher Scientific) [47].”
MethodA proteome signature of umbilical cord serum associated with congenital diaphragmatic hernia.
Tachi, A., Moriyama, Y., Tsuda, H., Miki, R., Ushida, T., Miura, M., Ito, Y., Imai, K., Nakano‐Kobayashi, T., Hayakawa, M., et al. (2020) · PubMed Central · doi:10.18999/nagjms.82.2.345 · Cited by 6 · see citing works
“Mass spectrometry and data analysis The procedure was performed in accordance with previous reports.(11,12) The total protein concentration of serum samples was assessed using the bicinchoninic acid assay (PierceTM BCA Protein Assay kit; Thermo Fisher Scientific Inc.”
MethodSelf-citationJin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., & Nusse, R. (2021) · doi:10.1101/2021.10.15.464616 · Cited by 2 · see citing works
“liver where they are also implicated in arresting the cell cycle (Matondo et al. 2018; Mizuno et al. 2019; Pandit et al. 2012; Qi et al. 2015).”
BackgroundNomoto, M., Kotani, T., Miki, R., Ushida, T., Imai, K., Iitani, Y., Tano, S., Wang, J., Moriyama, Y., Kobayashi, T., et al. (2021) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.21-37
Self-citation
- Authors
- Mizuno, M., Miki, R., Moriyama, Y., Ushida, T., Imai, K., Niimi, K., Nakano, T., Tsuda, H., Sumigama, S., Yamamoto, E., Senga, T., Iwase, A., Kikkawa, F., & Kotani, T.
- Affiliations
- Nagoya University (JP)
- Japanese Red Cross Nagoya Daiichi Hospital (JP)
- Department of Internal Medicine, Yahagigawa Hospital, Anjo, Aichi 444‑1164, Japan
- Corresponding author
- Kotani, Tomomi
- ORCID
- Venue
- Molecular Medicine Reports
- Publisher
- Spandidos Publications
- Published
- 2018-11-01
- Volume
- 19
- Issue
- 1
- Pages
- 293-301
- ISSN
- 1791-2997 (ISSN-L)
- 1791-3004
- PMC
- PMC6297733
- OpenAlex
- W2898754339
- Cited by
- 9
- References
- 30
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Molecular Medicine Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Nagoya University Repository (NAGOYA Repository) (submittedVersion, other-oa)
- Funders
- Queen's University
- Yamaguchi Endocrine Research Foundation
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Gestational Trophoblastic Disease Studies
- Keywords
- E2F8, human placenta, extravillous trophoblast, trophoblast invasion, placental development, cytotrophoblast, MMP-1, E2F transcription factors, HTR-8/SVneo cells, gene knockdown, cell adhesion, cell proliferation
- MeSH terms
- Cell Adhesion, Cell Cycle, Cell Movement, Cells, Cultured, Female, Humans, Placenta, Placentation, Pregnancy, Pregnancy Trimester, First, Repressor Proteins, RNA, Small Interfering, Cell Proliferation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
