E2f8 mediates tumor suppression in postnatal liver development
Open accessAbstract
E2F-mediated transcriptional repression of cell cycle-dependent gene expression is critical for the control of cellular proliferation, survival, and development. E2F signaling also interacts with transcriptional programs that are downstream of genetic predictors for cancer development, including hepatocellular carcinoma (HCC). Here, we evaluated the function of the atypical repressor genes E2f7 and E2f8 in adult liver physiology. Using several loss-of-function alleles in mice, we determined that combined deletion of E2f7 and E2f8 in hepatocytes leads to HCC. Temporal-specific ablation strategies revealed that E2f8's tumor suppressor role is critical during the first 2 weeks of life, which correspond to a highly proliferative stage of postnatal liver development. Disruption of E2F8's DNA binding activity phenocopied the effects of an E2f8 null allele and led to HCC. Finally, a profile of chromatin occupancy and gene expression in young and tumor-bearing mice identified a set of shared targets for E2F7 and E2F8 whose increased expression during early postnatal liver development is associated with HCC progression in mice. Increased expression of E2F8-specific target genes was also observed in human liver biopsies from HCC patients compared to healthy patients. In summary, these studies suggest that E2F8-mediated transcriptional repression is a critical tumor suppressor mechanism during postnatal liver development.
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, as well as polyploidy, suppress tumorigenesis.
“E2f7 and E2f8, as well as polyploidy, are known to suppress tumorigenesis (43–46).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [43]
The Discussion reports that loss of the E2F7/8 repressors leads to hepatocellular carcinoma in mice, and “Tumor suppressive function of E2F8” specifically identifies E2F8 as suppressing cancer initiation in developing livers. The paper also links E2F7/8 loss to reduced hepatocyte ploidy, but the passages do not establish that polyploidy itself suppresses tumorigenesis. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredE2f7 and E2f8 as well as polyploidy are known to suppress tumorigenesis.
“while E2f7 and E2f8 as well as polyploidy are known to suppress tumorigenesis (Kent et al. 2016;Moreno et al. 2021;Wilkinson et al. 2019;Zhang et al. 2018).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Kent et al. 2016
The “Tumor suppressive function of E2F8” section reports that E2f8 deletion promoted liver cancer in mice and that combined loss of E2f7 and E2f8 led to spontaneous liver cancer. The paper also says E2F8 is critical for hepatocyte polyploidy, but it does not establish that polyploidy itself suppresses tumorigenesis. Its tumor-suppression finding is specific to liver cancer in mice, rather than tumorigenesis generally. (LLM, conf=0.87)
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
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
Fast gapped-read alignment with Bowtie 2
Langmead, B., & Salzberg, S. L. (2012) · Nature Methods · doi:10.1038/nmeth.1923 · Cited by 56,400 · see citing works
Jemal, A., Bray, F., Ferlay, J., Ward, E., & Forman, D. (2011) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.20107 · Cited by 54,708 · see citing works
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012
Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015) · International Journal of Cancer · doi:10.1002/ijc.29210 · Cited by 28,766 · see citing works
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386 · see citing works
Cell cycle, CDKs and cancer: a changing paradigm
Malumbres, M., & Barbacid, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2602 · Cited by 3,957 · see citing works
Differential analysis of gene regulation at transcript resolution with RNA-seq
Trapnell, C., Hendrickson, D. G., Sauvageau, M., Goff, L., Rinn, J. L., & Pachter, L. (2013) · Nature Biotechnology · doi:10.1038/nbt.2450 · Cited by 3,492 · see citing works
Emerging roles of E2Fs in cancer: an exit from cell cycle control
Chen, H., Tsai, S., & Leone, G. W. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2696 · Cited by 1,019 · see citing works
Self-citationGenome‐wide molecular profiles of HCV‐induced dysplasia and hepatocellular carcinoma†
Wurmbach, E., Chen, Y., Khitrov, G., Zhang, W., Roayaie, S., Schwartz, M., Fiel, M. I., Thung, S. N., Mazzaferro, V., Bruix, J., et al. (2007) · Hepatology · doi:10.1002/hep.21622 · Cited by 721 · see citing works
The 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 · see citing works
Self-citationProliferative and Nonproliferative Lesions of the Rat and Mouse Hepatobiliary System
Thoolen, B., Maronpot, R., Harada, T., Nyska, A., Rousseaux, C., Nolte, T., Malarkey, D., Kaufmann, W., Küttler, K., Deschl, U., et al. (2010) · Toxicologic pathology (Print) · doi:10.1177/0192623310386499 · Cited by 614 · see citing works
A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice
Mitchell, C., & Willenbring, H. (2008) · Nature Protocols · doi:10.1038/nprot.2008.80 · Cited by 577 · see citing works
Genetics of hepatocellular tumors
Laurent‐Puig, P., & Zucman‐Rossi, J. (2006) · Oncogene · doi:10.1038/sj.onc.1209547 · Cited by 317 · see citing works
Life and death decisions by the E2F transcription factors
Iaquinta, P. J., & Lees, J. A. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.10.006 · Cited by 304 · see citing works
Preparation, Culture, and Immortalization of Mouse Embryonic Fibroblasts
Xu, J. (2005) · Current Protocols in Molecular Biology · doi:10.1002/0471142727.mb2801s70 · Cited by 300 · see citing works
E2F7, a novel E2F featuring DP‐independent repression of a subset of E2F‐regulated genes
Stefano, L. D., Jensen, M. R., & Helin, K. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg613 · Cited by 272 · see citing works
Atypical E2Fs: new players in the E2F transcription factor family
Lammens, T., Li, J., Leone, G. W., & Veylder, L. D. (2009) · Trends in Cell Biology · doi:10.1016/j.tcb.2009.01.002 · Cited by 228 · see citing works
Self-citationde Bruin, A., Maiti, B., Jakoi, L., Timmers, C., Buerki, R., & Leone, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308105200 · Cited by 221 · see citing works
Self-citationSynergistic Function of E2F7 and E2F8 Is Essential for Cell Survival and Embryonic Development
Li, J., Ran, C., Li, E., Gordon, F., Comstock, G., Siddiqui, H., Cleghorn, W. M., Chen, H., Kornacker, K., Liu, C., et al. (2008) · Developmental Cell · doi:10.1016/j.devcel.2007.10.017 · Cited by 221 · 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 · see citing works
Self-citationEfficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse
Schuler, M. J., Dierich, A., Chambon, P., & METZGER, D. (2004) · genesis · doi:10.1002/gene.20039 · Cited by 175 · see citing works
Functional antagonism between E2F family membersPreprint
Frolov, M. V., Huen, D. S., Nolan-Stevaux, O., Dimova, D. K., Balczarek-Strang, K., Elsdon, M. J., & Dyson, N. J. (2001) · Genes & Development · doi:10.1101/gad.903901 · Cited by 168 · see citing works
E2F8 is essential for polyploidization in mammalian cells
Pandit, S. K., Westendorp, B., Nantasanti, S., van Liere, E., Tooten, P. C. J., Cornelissen, P. W. A., Toussaint, M. J. M., Lamers, W. H., & de Bruin, A. (2012) · Nature Cell Biology · doi:10.1038/ncb2585 · Cited by 168 · cited 7× · see citing works
“All other lines were clearly demonstrate that normal hepatocytes lacking E2F8 proliferate avidly (13, 15).”
InfluentialSelf-citationCanonical and atypical E2Fs regulate the mammalian endocycle
Chen, H.-Z., Ouseph, M. M., Li, J., Pécot, T., Chokshi, V., Kent, L., Bae, S., Byrne, M., Duran, C., Comstock, G., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2595 · Cited by 161 · see citing works
Self-citationDiRE: identifying distant regulatory elements of co-expressed genes
Gotea, V., & Ovcharenko, I. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn300 · Cited by 127 · see citing works
The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescencePreprint
Aksoy, O., Chicas, A., Zeng, T., Zhao, Z., McCurrach, M. E., Wang, X., & Lowe, S. W. (2012) · Genes & Development · doi:10.1101/gad.196238.112 · Cited by 127 · see citing works
E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7
Logan, N. A., Graham, A., Zhao, X., Fisher, R., Maiti, B., Leone, G. W., & Thangue, N. B. L. (2005) · Oncogene · doi:10.1038/sj.onc.1208703 · Cited by 125 · see citing works
Self-citationE2F7 represses a network of oscillating cell cycle genes to control S-phase progression
Westendorp, B., Mokry, M., Groot Koerkamp, M. J. A., Holstege, F. C. P., Cuppen, E., & de Bruin, A. (2012) · Nucleic Acids Research · doi:10.1093/nar/gkr1203 · Cited by 125 · see citing works
Self-citationA role for E2F6 in distinguishing G1/S- and G2/M-specific transcriptionPreprint
Giangrande, P. H., Zhu, W., Schlisio, S., Sun, X., Mori, S., Gaubatz, S., & Nevins, J. R. (2004) · Genes & Development · doi:10.1101/gad.1239304 · Cited by 121 · see citing works
E2F8 contributes to human hepatocellular carcinoma via regulating cell proliferation.
Deng, Q., Wang, Q., Zong, W., Zheng, D.-L., Wen, Y., Wang, K.-S., Teng, X.-M., Zhang, X., Huang, J., & Han, Z.-G. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3082 · Cited by 111 · see citing works
Atypical 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 · see citing works
Self-citationLiver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy
Mayhew, C. N., Bosco, E. E., Fox, S. R., Okaya, T., Tarapore, P., Schwemberger, S. J., Babcock, G. F., Lentsch, A. B., Fukasawa, K., & Knudsen, E. S. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4221 · Cited by 101 · see citing works
E2F8 as a Novel Therapeutic Target for Lung Cancer.
Park, S.-A., Platt, J., Lee, J.-W., López-Giráldez, F., Herbst, R., & Koo, J. (2015) · Journal of the National Cancer Institute · doi:10.1093/jnci/djv151 · Cited by 97 · see citing works
Diversity within the pRb pathway: is there a code of conduct?
Munro, S., Carr, S. M., & Thangue, N. B. L. (2012) · Oncogene · doi:10.1038/onc.2011.603 · Cited by 88 · see citing works
RB Loss Abrogates Cell Cycle Control and Genome Integrity to Promote Liver Tumorigenesis
Mayhew, C. N., Carter, S. L., Fox, S. R., Sexton, C. R., Reed, C. A., Srinivasan, S. V., Liu, X., Wikenheiser‐Brokamp, K. A., Boivin, G. P., Lee, J., et al. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.06.025 · Cited by 85 · see citing works
Developmental defects and tumor predisposition in Rb mutant mice
Vooijs, M., & Berns, A. J. M. (1999) · Oncogene · doi:10.1038/sj.onc.1202999 · Cited by 77 · see citing works
Cell proliferation in the absence of E2F1-3
Wenzel, P. L., Chong, J.-L., Sáenz-Robles, M. T., Ferrey, A., Hagan, J. P., Gomez, Y. M., Rajmohan, R., Sharma, N., Chen, H., Pipas, J. M., et al. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.12.025 · Cited by 63 · see citing works
Self-citationCertain Aspects of Hepatocarcinogenesis in the Infant Mouse Model
Vesselinovitch, S. D. (1987) · Toxicologic Pathology · doi:10.1177/019262338701500216 · Cited by 25 · see citing works
Niwa‐Kawakita, M., Abramowski, V., Kalamarides, M., Thomas, G. D., & Giovannini, M. (2000) · genesis · doi:10.1002/(sici)1526-968x(200002)26:2 · Cited by 22 · see citing works
Infant mouse as a sensitive bioassay system for carcinogenicity of N-nitroso compounds.
Vesselinovitch, S. D. (1980) · PubMed · Cited by 18 · see citing works
E2F8 is a nonreceptor activator of heterotrimeric G proteins
Hagemann, I. S., Narzinski, K., & Baranski, T. (2007) · Journal of Molecular Signaling · doi:10.1186/1750-2187-2-3 · Cited by 7 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Laurent-Puig P, Zucman-Rossi J. Genet- ics of hepatocellular tumors. Oncogene. 2006;25(27):3778-3786.
- Postic C, Magnuson MA. DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis. 2000;26(2):149-150.
Cited by
Sorted by citations
The broken cycle: E2F dysfunction in cancer
Kent, L. N., & Leone, G. W. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0143-7 · Cited by 786 · see citing works
Self-citationThe Polyploid State Plays a Tumor-Suppressive Role in the Liver
Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H.-C., Sehgal, A., Nguyen, L. H., Zhang, Y., Gopal, P., Tarlow, B. D., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.010 · Cited by 180 · see citing works
The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase
Sanghvi, V. R., Leibold, J., Mina, M., Mohan, P., Berishaj, M., Li, Z., Miele, M. M., Lailler, N., Zhao, C., de Stanchina, E., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.031 · Cited by 155 · see citing works
The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice
Wilkinson, P. D., Delgado, E. R., Alencastro, F., Leek, M. P., Roy, N., Weirich, M. P., Stahl, E. C., Otero, P. A., Chen, M. I., Brown, W. K., et al. (2019) · Hepatology · doi:10.1002/hep.30286 · Cited by 135 · see citing works
Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma
Kent, L. N., Bae, S., Tsai, S., Tang, X., Srivastava, A., Koivisto, C. S., Martin, C. K., Ridolfi, E., Miller, G. C., Zorko, S. M., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci87583 · Cited by 126 · see citing works
Self-citationBifidobacterium Strain-Specific Enhances the Efficacy of Cancer Therapeutics in Tumor-Bearing Mice
Yoon, Y., Kim, G., Jeon, B., Fang, S., & Park, H. (2021) · Cancers · doi:10.3390/cancers13050957 · Cited by 91 · see citing works
Ma, Y., Lv, Z., Yu, F., Chang, Z., Cong, X., Zhong, X., Lu, G., Zhu, J., & Fu, D. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0927-8 · Cited by 74 · see citing works
Sladky, V. C., Knapp, K., Soratroi, C., Heppke, J., Eichin, F., Rocamora-Reverte, L., Szabo, T., Bongiovanni, L., Westendorp, B., Moreno, E., et al. (2020) · Developmental Cell · doi:10.1016/j.devcel.2019.12.016 · Cited by 55 · see citing works
Self-citationRole of E2F transcription factor in oral cancer: Recent insight and advancements
Kassab, A., Gupta, I., & Moustafa, A. A. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.03.004 · Cited by 68 · see citing works
Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation
Cuitiño, M. C., Pécot, T., Sun, D., Kladney, R. D., Okano‐Uchida, T., Shinde, N., Saeed, R., Perez-Castro, A., Webb, A., Liu, T., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.004 · Cited by 63 · see citing works
Self-citationPolyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury
Wilkinson, P. D., Alencastro, F., Delgado, E. R., Leek, M. P., Weirich, M. P., Otero, P. A., Roy, N., Brown, W. K., Oertel, M., & Duncan, A. W. (2019) · The American Journal of Pathology · doi:10.1016/j.ajpath.2019.02.008 · Cited by 60 · see citing works
Cyclin F‐dependent degradation of E2F7 is critical for DNA repair and G2‐phase progression
Yuan, R., Liu, Q., Segeren, H. A., Yuniati, L., Guardavaccaro, D., Lebbink, R. J., Westendorp, B., & de Bruin, A. (2019) · The EMBO Journal · doi:10.15252/embj.2018101430 · Cited by 60 · see citing works
Self-citationPromising diagnostic and prognostic value of E2Fs in human hepatocellular carcinoma
Huang, Y., Ning, G., Chen, L., Lian, Y., Gu, Y., Wang, J., Chen, D., Wei, H. J., & Huang, Y. (2019) · Cancer Management and Research · doi:10.2147/cmar.s182001 · Cited by 59 · see citing works
E2F8 is a Potential Therapeutic Target for Hepatocellular Carcinoma
Lv, Y., Xiao, J., Liu, J., & Xing, F. (2017) · Journal of Cancer · doi:10.7150/jca.18255 · Cited by 50 · see citing works
PIDDosome‐induced p53‐dependent ploidy restriction facilitates hepatocarcinogenesis
Sladky, V. C., Knapp, K., Szabo, T., Braun, V. Z., Bongiovanni, L., van den Bos, H., Spierings, D., Westendorp, B., Curinha, A., Stojaković, T., et al. (2020) · EMBO Reports · doi:10.15252/embr.202050893 · Cited by 43 · see citing works
Self-citationPolyploidy control in hepatic health and disease
Sladky, V. C., Eichin, F., Reiberger, T., & Villunger, A. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.06.030 · Cited by 49 · see citing works
Gene repression through epigenetic modulation by PPARA enhances hepatocellular proliferation
Aibara, D., Takahashi, S., Yagai, T., Kim, D., Brocker, C. N., Levi, M., Matsusue, K., & Gonzalez, F. J. (2022) · iScience · doi:10.1016/j.isci.2022.104196 · Cited by 41 · see citing works
Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma
Kumar, D., Das, M., Oberg, A., Sahoo, D., Wu, P., Sauceda, C., Jih, L., Ellies, L. G., Langiewicz, M., Sen, S., et al. (2022) · Advanced Science · doi:10.1002/advs.202105120 · Cited by 39 · see citing works
Metformin induces cell cycle arrest at the G1 phase through E2F8 suppression in lung cancer cells
Jin, D., Kim, Y., Lee, B. B., Han, J., Kim, H. K., Shim, Y. M., & Kim, D.-H. (2017) · Oncotarget · doi:10.18632/oncotarget.21552 · Cited by 37 · see citing works
Integrated analysis of the E2F transcription factors across cancer types
Wang, H., Wang, X., Xu, L., Zhang, J., & Cao, H. (2020) · Oncology Reports · doi:10.3892/or.2020.7504 · Cited by 39 · see citing works
E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice
Moreno, E., Toussaint, M. J. M., van Essen, S. C., Bongiovanni, L., van Liere, E. A., Koster, M. H., Yuan, R., van Deursen, J. M., Westendorp, B., & de Bruin, A. (2021) · Hepatology · doi:10.1002/hep.31259 · Cited by 37 · see citing works
Self-citationSegeren, H. A., van Rijnberk, L. M., Moreno, E., Riemers, F. M., van Liere, E. A., Yuan, R., Wubbolts, R., de Bruin, A., & Westendorp, B. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108449 · Cited by 36 · see citing works
Self-citationChk1 and 14‐3‐3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest
Yuan, R., Vos, H. R., van Es, R. M., Chen, J., Burgering, B. M. T., Westendorp, B., & de Bruin, A. (2018) · The EMBO Journal · doi:10.15252/embj.201797877 · Cited by 33 · see citing works
Self-citationDifferential roles for diploid and polyploid hepatocytes in acute and chronic liver injury
Wilkinson, P. D., & Duncan, A. (2020) · Seminars in liver disease (Print) · doi:10.1055/s-0040-1719175 · Cited by 25 · see citing works
Deregulated E2F Activity as a Cancer-Cell Specific Therapeutic Tool
Nakajima, R., Zhao, L., Zhou, Y., Shirasawa, M., Uchida, A., Murakawa, H., Fikriyanti, M., Iwanaga, R., Bradford, A. P., Araki, K., et al. (2023) · Genes · doi:10.3390/genes14020393 · Cited by 30 · 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
Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases
Donné, R., Sangouard, F., Celton‐Morizur, S., & Desdouets, C. (2021) · Cancers · doi:10.3390/cancers13205151 · Cited by 28 · see citing works
Centriole signaling restricts hepatocyte ploidy to maintain liver integrityPreprint
Sladky, V. C., Akbari, H., Tapias-Gomez, D., Evans, L. T., Drown, C. G., Strong, M. A., LoMastro, G. M., Larman, T. C., & Holland, A. (2022) · Genes & Development · doi:10.1101/gad.349727.122 · Cited by 22 · see citing works
Significance of RB Loss in Unlocking Phenotypic Plasticity in Advanced Cancers
Venkadakrishnan, V. B., Yamada, Y., Weng, K., Idahor, O., & Beltran, H. (2023) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-23-0045 · Cited by 28 · see citing works
Schlafen 5 as a novel therapeutic target in pancreatic ductal adenocarcinoma
Fischietti, M., Eckerdt, F., Blyth, G. T., Arslan, A. D., Mati, W. M., Oku, C. V., Perez, R. E., Lee-Chang, C., Kościuczuk, E. M., Saleiro, D., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01761-1 · Cited by 24 · see citing works
Emerging role of E2F8 in human cancer
Lee, D. Y., Chun, J. N., Cho, M., So, I., & Jeon, J. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166745 · Cited by 24 · see citing works
Liu, Z., Zhou, W., Lin, C., Wang, X., Zhang, X., Zhang, Y., Yang, R., Chen, W., & Cao, W. (2020) · Aging · doi:10.18632/aging.202268 · Cited by 23 · see citing works
Atypical E2Fs inhibit tumor angiogenesis
Weijts, B., Westendorp, B., Hien, B., Martínez-López, L., Zijp, M., Thurlings, I., Thomas, R., Schulte-Merker, S., Bakker, W., & de Bruin, A. (2017) · Oncogene · doi:10.1038/onc.2017.336 · Cited by 19 · see citing works
Self-citationE2F transcription factor 8 promotes proliferation and radioresistance in glioblastoma
Yu, H., Zhang, D., Li, Z., & Wang, M. (2020) · Pathology - Research and Practice · doi:10.1016/j.prp.2020.153030 · Cited by 22 · see citing works
Varone, E., Retini, M., Cherubini, A., Chernorudskiy, A. L., Marrazza, A., Guidarelli, A., Cagnotto, A., Beeg, M., Gobbi, M., Fumagalli, S., et al. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07426-1 · Cited by 20 · see citing works
Liao, R., Qi, Z., Tang, R. N., Wang, R., & Wang, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.714390 · Cited by 20 · see citing works
Liu, K., Wang, L., Lou, Z., Guo, L., Xu, Y., Qi, H., Fang, Z., Mei, L., Chen, X., Zhang, X., et al. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115854 · Cited by 20 · see citing works
CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I
Palmer, N., Talib, S. Z. A., Ratnacaram, C. K., Low, D. H. P., Bisteau, X., Lee, J., Pfeiffenberger, E., Wollmann, H., Tan, J. H. L., Wee, S., et al. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201903125 · Cited by 17 · see citing works
Enhancer methylation dynamics drive core transcriptional regulatory circuitry in pan-cancer
Xu, P., Li, X., Sun, J., Xiong, Z., Hu, H., Ning, S., & Zhi, H. (2022) · Oncogene · doi:10.1038/s41388-022-02359-x · Cited by 17 · see citing works
Ploidy dynamics increase the risk of liver cancer initiation
Müller, M., May, S., & Bird, T. G. (2021) · Nature Communications · doi:10.1038/s41467-021-21897-8 · Cited by 10 · see citing works
Lü, Y., Zhang, J., Li, L., Li, S., & Yang, Z. (2020) · Bioscience Reports · doi:10.1042/bsr20193212 · Cited by 15 · see citing works
Bongiovanni, L., Andriessen, A., Silvestri, S., Porcellato, I., Brachelente, C., & de Bruin, A. (2021) · Frontiers in Veterinary Science · doi:10.3389/fvets.2021.705359 · Cited by 14 · see citing works
Liao, R., Xie, B., Cui, J., Qi, Z., Xue, S., & Wang, Y. (2021) · Bioengineered · doi:10.1080/21655979.2021.1972194 · Cited by 14 · see citing works
Atypical E2f functions are critical for pancreas polyploidization
Matondo, R. B., Moreno, E., Toussaint, M. J. M., Tooten, P. C. J., van Essen, S. C., van Liere, E. A., Youssef, S. A., Bongiovanni, L., & de Bruin, A. (2018) · PLOS ONE · doi:10.1371/journal.pone.0190899 · Cited by 14 · see citing works
The Ploidy State as a Determinant of Hepatocyte Proliferation
Wilson, S. R., & Duncan, A. W. (2023) · Seminars in liver disease (Print) · doi:10.1055/a-2211-2144 · Cited by 11 · see citing works
Cellular polyploidy in organ homeostasis and regeneration
Fang, J.-T., de Bruin, A., Villunger, A., Schiffelers, R., Lei, Z., & Sluijter, J. (2022) · Protein & Cell · doi:10.1093/procel/pwac064 · Cited by 14 · see citing works
Moreno, E., Pandit, S. K., Toussaint, M. J. M., Bongiovanni, L., Harkema, L., van Essen, S. C., van Liere, E. A., Westendorp, B., & de Bruin, A. (2021) · Cancers · doi:10.3390/cancers13092033 · Cited by 12 · see citing works
Self-citationRegulation of the transcription factor E2F8 gene expression in bovine ovarian cells
Morrell, B. C., Zhang, L., Schütz, L. F., Perego, M. C., Maylem, E. R. S., & SPICER, L. J. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110572 · Cited by 12 · see citing works
BmE2F1 regulates endoreplication of silk gland cells in silkworm, Bombyx mori
Zhou, L., Liu, S., Li, C., Zhou, W., Dai, F., & Tong, X. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.138916 · Cited by 11 · see citing works
Xu, W., Lu, X., Liu, J., Chen, Q., Huang, X., Huang, K., Liu, H., Zhu, W., & Zhang, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.700700 · Cited by 11 · see citing works
Self-citationCDC6 : A novel canine tumour biomarker detected in circulating extracellular vesicles
Andriessen, A., Bongiovanni, L., Driedonks, T. A. P., van Liere, E. A., Seijger, A., Hegeman, C. V., van Nimwegen, S. A., Galac, S., Westendorp, B., Hoen, E. N. M. N., et al. (2021) · Veterinary and Comparative Oncology · doi:10.1111/vco.12781 · Cited by 11 · see citing works
Self-citationCucchi, D. G. J., Bachas, C., van den Heuvel‐Eibrink, M. M., Arentsen-Peters, S. T. C. J. M., Kwidama, Z. J., Schuurhuis, G. J., Assaraf, Y. G., de Haas, V., Kaspers, G. J. L., & Cloos, J. J. (2020) · Cancers · doi:10.3390/cancers12051247 · Cited by 11 · see citing works
Group crisis intervention in a school setting following an attempted suicide.
Newman, E. C. (2000) · PubMed · Cited by 11 · see citing works
Transcription factor E2F8 is a therapeutic target in the basal-like subtype of breast cancer
Zheng, J., Huang, J., Xia, J., Zhou, W., Dai, L., Lin, S., Gao, L., & Zou, C. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1038787 · Cited by 11 · see citing works
Mechanisms driving resistance to oxidative stress during endometrial stromal cell decidualization
Thapa, R., & Monsivais, D. (2025) · Biology of Reproduction · doi:10.1093/biolre/ioaf198 · Cited by 9 · see citing works
Wei, T., Liu, J., Ma, S., Wang, M., Yuan, Q., Huang, A., Wu, Z., Shang, D., & Yin, P. (2023) · Metabolites · doi:10.3390/metabo13111116 · Cited by 8 · see citing works
Yang, A., Liu, L. G., Chen, M., Liu, F., You, H., Liu, L., Yang, H., Xun, Y., Liu, J., Wang, R., et al. (2019) · PubMed Central · Cited by 8 · see citing works
Hepatocyte ploidy modulation in liver cancer
Duncan, A. W. (2020) · EMBO Reports · doi:10.15252/embr.202051922 · Cited by 5 · see citing works
NT5DC2 is a novel prognostic marker in human hepatocellular carcinoma
Chen, J., Cao, J., Wang, P., & He, X. (2020) · Oncology Letters · doi:10.3892/ol.2020.11931 · Cited by 7 · see citing works
Liu, Z., Feng, C., Li, C., He, T., Wu, G., Fu, C., Li, H., Shen, M., & Liu, H. (2023) · The FASEB Journal · doi:10.1096/fj.202301464r · Cited by 6 · see citing works
Luo, H., Tao, C., Long, X., Zhu, X., & Huang, K. (2021) · Bioengineered · doi:10.1080/21655979.2021.1985340 · Cited by 6 · see citing works
Self-citationChronobiology of neurotropic viruses: rhythmic viral entry and arrhythmic host clocks
Zeng, S., Zhang, Q., Yang, X., Lv, L., Zhang, Y., Zhang, Z., Wang, Q., Luo, M., Dorf, M. E., Li, S., et al. (2026) · Cell Discovery · doi:10.1038/s41421-026-00867-8 · Cited by 5 · see citing works
The E2F family: a ray of dawn in cardiomyopathy
Wei, J., Gao, C., Lu, C., Wang, L., Dong, D., & Sun, M. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-024-05063-4 · Cited by 6 · see citing works
Huang, F., Li, K., Chen, Z., Cui, Z., Hankey, W., Fang, K., Yan, J., Wang, H., Jin, V. X., Dong, Y., et al. (2024) · Oncogene · doi:10.1038/s41388-024-03239-2 · Cited by 5 · see citing works
Inhibition of polyploidization in Pten‐deficient livers reduces steatosis
Moreno, E., Matondo, A. B., Bongiovanni, L., van de Lest, C. V. D., Molenaar, M. R., Toussaint, M., van Essen, S. C., Houweling, M., Helms, J. B., Westendorp, B., et al. (2022) · Liver international (Print) · doi:10.1111/liv.15384 · Cited by 4 · see citing works
Self-citationWang, L., Chen, Y., Chen, R., Mao, F., Sun, Z. S., & Liu, X. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.102948 · Cited by 5 · see citing works
Comprehensive bioinformatics analysis of the E2F family in human clear cell renal cell carcinoma
Liu, Z.-G., Su, J., Liu, H., Yang, X., Yang, X., Wei, Y., Zhu, X., Song, Y., Zhao, X., & Guo, H. (2022) · Oncology Letters · doi:10.3892/ol.2022.13471 · Cited by 5 · see citing works
Karan, D., Dubey, S., Gunewardena, S., Iczkowski, K. A., Singh, M., Liu, P., Poletti, A., Choo, Y., Chen, H., & Hamann, M. T. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13637 · Cited by 4 · see citing works
Self-citationCluzet, V., Airaud, É., Tête, A., Devillers, M. M., Petit, F., Leary, A. F., Pierre, A., Li, H., Day, C., Weyemi, U., et al. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0957 · Cited by 4 · see citing works
E2F Transcription Factors in Cancer, More than the Cell Cycle
Broeker, C. D., & Andrechek, E. R. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00102-x · Cited by 4 · see citing works
Dietary fat/cholesterol-sensitive PKCβ-RB signaling: Potential role in NASH/HCC axis
Huang, W., Mehta, D., Sif, S., Kent, L. N., Jacob, S. T., Ghoshal, K., & Mehta, K. D. (2017) · Oncotarget · doi:10.18632/oncotarget.17890 · Cited by 4 · see citing works
Self-citationLuo, Z., Wu, J., Xu, B., Wu, D., Zhong, Y., Hao, M., Xu, Y., Yang, J., Wang, Y., Lauschke, V. M., et al. (2026) · Biomaterials · doi:10.1016/j.biomaterials.2026.124089 · Cited by 3 · see citing works
To, B., Broeker, C. D., Jhan, J.-R., Garcia-Lerena, J., Vusich, J., Rempel, R. E., Rennhack, J. P., Hollern, D. P., Jackson, L., Judah, D., et al. (2024) · Oncogene · doi:10.1038/s41388-024-03172-4 · Cited by 4 · see citing works
Xu, X., Zhang, D., Zhao, K., Liu, Z., Ren, X., Zhang, X., Lü, Z., Qin, C., Wang, J., & Wang, S. (2023) · Toxicology · doi:10.1016/j.tox.2023.153681 · Cited by 3 · see citing works
Multi-dimension metabolic prognostic model for gastric cancer
Feng, W., Xu, B., & Zhu, X. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1228136 · Cited by 3 · see citing works
Xie, L., Shu, Y., Ye, M., & Li, Y. (2024) · Pathology - Research and Practice · doi:10.1016/j.prp.2024.155358 · Cited by 3 · see citing works
Segeren, H. A., van Rijnberk, L. M., Moreno, E., Riemers, F., van Liere, E. V., Yuan, R.-X., Wubbolts, R., de Bruin, A., & Westendorp, B. (2020) · bioRxiv · doi:10.1101/2020.03.19.998674 · Cited by 32 · see citing works
Self-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
Wang, N., Hao, F., Zhang, Y., Xu, W., Chen, Y., Fei, X., & Wang, J. (2022) · Journal of Cancer · doi:10.7150/jca.72890 · Cited by 2 · see citing works
OSgc: A Web Portal to Assess the Performance of Prognostic Biomarkers in Gastric Cancer
Xie, L., Wang, Q., Yan, Z., Han, Y., Ma, X., Li, H., Zhang, L., Li, X., & Guo, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.856988 · Cited by 2 · see citing works
Polyploidy in Liver Function, Mitochondrial Metabolism, and Cancer
Delgado, E. R., Stahl, E., Roy, N., Wilkinson, P. D., & Duncan, A. (2020) · doi:10.1002/9781119436812.ch47 · Cited by 1 · see citing works
PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesisPreprint
Sladky, V. C., Knapp, K., Szabo, T., Bongiovanni, L., van den Bos, H., Spierings, D., Westendorp, B., Stojaković, T., Scharnagl, H., Timelthaler, G., et al. (2020) · bioRxiv · doi:10.1101/2020.05.13.092486 · Cited by 1 · see citing works
Self-citationYang, C., Cheng, D., Wang, S., Wang, B., Li, Y., Wang, G., Wang, X., Shi, C., Tian, Y., Zhu, K., et al. (2025) · Journal of Cancer · doi:10.7150/jca.110981 · Cited by 1 · see citing works
Diploid hepatocytes resist acetaminophen-induced liver injury through suppressed JNK signaling
Wilson, S. R., Delgado, E. R., Alencastro, F., Loewenstein, R. L., Leek, M. P., Peters, L. R., Kamel, K., Wilkinson, P. D., Jain, S., Locker, J. D., et al. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08448-z · Cited by 1 · see citing works
p53 and RB Cooperate to Suppress Transposable ElementsPreprint
Lopez, O. M., Zhang, M. H., Hendrickson, P. G., Huang, J., Daniel, A. R., Blackmer, J. E., Luo, L., Attardi, L. D., Corcoran, D. L., & Kirsch, D. G. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.06.527304 · Cited by 1 · see citing works
Piekos, S. C. (2018) · OpenCommons at University of Connecticut (University of Connecticut)
Komori, H., Iwanaga, R., Bradford, A. P., Araki, K., & Ohtani, K. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.82448
Expression and prognostic value of E2F family members in gastric cancerPreprint
Li, H., Zhao, S., Shen, L., Wang, P., Liu, S., Ma, Y., Liang, Z., Wang, G., Lv, J., & Qiu, W. (2020) · Research Square · doi:10.21203/rs.3.rs-45670/v1
Cluzet, V., Airaud, É., Devillers, M. M., Petit, F., Leary, A. F., Pierre, A., Li, H., Day, C., Weyemi, U., Chauvin, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.02.601506
Zhang, F., Sun, Z., Zhang, Z., Jiang, K., Wei, B., Yu, X., Zuo, Y., & Ren, S. (2025) · Discover Oncology · doi:10.1007/s12672-025-02615-y
Biological Features Underlying Factor-Specific Predictability of Cross-Species Regulatory OccupancyPreprint
Wang, Y., Liu, G., Wang, Y., & Zhang, Y. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.14.718438
Barbosa, M. G., Vos, D., Verzijl, C. R. C., Heida, A., Bakker, M., Kloosterhuis, N., Koster, M. H., Smit, M., Fajardo, A., Struik, D., et al. (2026) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2026.101788
Yin, M., Bo, X., Li, Y., Yu, S., Lin, Z., Wang, M., Wu, J., Zhou, M., Kong, L., Zhu, Y., et al. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08375-9
- Authors
- Kent, L. N., Rakijas, J. B., Pandit, S. K., Westendorp, B., Chen, H.-Z., Huntington, J. T., Tang, X., Bae, S., Srivastava, A., Senapati, S., Koivisto, C., Martin, C. K., Cuitino, M. C., Perez, M., Clouse, J. M., Chokshi, V., Shinde, N., Kladney, R., Sun, D., Perez-Castro, A., Matondo, R. B., Nantasanti, S., Mokry, M., Huang, K., Machiraju, R., Fernandez, S., Rosol, T. J., Coppola, V., Pohar, K. S., Pipas, J. M., Schmidt, C. R., de Bruin, A., & Leone, G.
- Affiliations
- The Ohio State University (US)
- Utrecht University (NL)
- University of Pittsburgh (US)
- ORCID
- Kent, Lindsey N.
- Rakijas, Jessica B.
- Pandit, Shusil K.
- Westendorp, Bart
- Huntington, Justin T.
- Tang, Xing
- Bae, Sooin
- Srivastava, Arunima
- Senapati, Shantibhusan
- Koivisto, Christopher
- Martin, Chelsea K.
- Perez, Miguel
- Huang, Kun
- Machiraju, Raghu
- Rosol, Thomas J.
- Coppola, Vincenzo
- Pohar, Kamal S.
- Pipas, James M.
- Schmidt, Carl R.
- Leone, Gustavo
- Venue
- Journal of Clinical Investigation
- Published
- 2016-07-25
- Volume
- 126
- Issue
- 8
- Pages
- 2955-2969
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4966321
- OpenAlex
- W2503633139
- Cited by
- 95
- References
- 41
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 13 · 2022: 11 · 2021: 14 · 2020: 16 · 2019: 10 · 2018: 6 · 2017: 5
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- IslandScholar (University of Prince Edward Island) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Universiteit Utrecht
- KWF Kankerbestrijding
- National Institutes of Health
- National Cancer Institute (R01CA098956, R01CA121275, P01CA097189, P30CA016058)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- E2F8, E2F7, E2F transcription factors, hepatocellular carcinoma, tumor suppression, postnatal liver development, hepatocytes, transcriptional repression, DNA-binding activity, chromatin occupancy, E2F target genes, liver cancer progression, mouse model
- MeSH terms
- Protein Domains, Alleles, Animals, Biopsy, Cell Survival, DNA, Female, Genotype, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Male, Protein Binding, Repressor Proteins, Signal Transduction, Gene Deletion, Sequence Analysis, RNA, Oligonucleotide Array Sequence Analysis, Hepatocytes, Cell Proliferation, E2F7 Transcription Factor, Mice
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
