T-box Transcription Factor Tbx3 Contributes to Human Hepatocellular Carcinoma Cell Migration and Invasion by Repressing E-Cadherin Expression
Open accessAbstract
Tbx3, a member of the T-box family of transcription factors, contributes directly to tumor formation, migration, and invasion. However, the role of Tbx3 in the metastasis of HCC remains unclear. In the present study, Tbx3 expression was detected in HCC tissues and cells by Western blot, and Tbx3 expression was regulated by use of siRNAs or lentivirus-mediated vectors. Here we found that Tbx3 protein expression increased in HCC tissues and cell lines. Tbx3 expression was positively associated with multiple tumor nodes, venous infiltration, and advanced TNM tumor stage. Survival analysis demonstrated that Tbx3 expression was an independent prognostic factor for HCC patients. In vitro assays further validated that Tbx3 indeed prompted HCC cell migration and invasion. In addition, Tbx3 expression was negatively related with E-cadherin expression in HCC tissues. Mechanically, Tbx3 inhibited the expression of E-cadherin, and then facilitated epithelial‐mesenchymal transition (EMT) of HCC cells. Furthermore, the effect of Tbx3 knockdown on HCC cells was attenuated by E-cadherin knockdown. In conclusion, Tbx3 may be a novel prognostic factor, and it contributes to HCC cell migration, invasion, and EMT by repressing E-cadherin expression. Thus, Tbx3 may be recommended as a therapeutic target for HCC patients.
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Human HepG2 cells express Tbx3 and can be used as a model to test the effect of mutating TBX3 sites in hepatocyte enhancer sequences.
“Human HepG2 cells express Tbx3 and can therefore be used as a model to test the effect of mutating TBX3 sites in hepatocyte enhancer sequences45.”
From Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation (2024) · cites this paper as [45]
The Results section, “Expression of Tbx3 in HCC Tissues and Cell Lines” (page not supplied), reports Tbx3 protein expression in HepG2 cells. The paper does not establish HepG2 as a model for testing mutations of TBX3 sites in hepatocyte enhancer sequences; its experiments address HCC cell migration and invasion. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHuman HepG2 cells express Tbx3 and may therefore serve as a model to test the effect of mutating Tbx3 sites in hepatocyte enhancer sequences.
“Human HepG2 cells express Tbx3 and may therefore serve as a model to test the effect of mutating Tbx3 sites in hepatocyte enhancer sequences63.”
From Enhancer grammar of liver cell types and hepatocyte zonation states (2022) · cites this paper as [63]
The Results section, “Expression of Tbx3 in HCC Tissues and Cell Lines” (page unavailable), reports Tbx3 protein expression in HepG2 cells. The paper does not address mutating Tbx3 sites in hepatocyte enhancer sequences or evaluate HepG2 for that purpose; the proposed use is an inference beyond what this source establishes. (LLM, conf=0.84)
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Cites
1 retracted
Tu, K., Dou, C., Zheng, X. M., Li, C., Yang, W., Yao, Y., & Liu, Q. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-938 · Cited by 40 · see citing works
RetractedTwist, a Master Regulator of Morphogenesis, Plays an Essential Role in Tumor Metastasis
Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R., Côme, C., Savagner, P., Gitelman, I., Richardson, A. L., & Weinberg, R. A. (2004) · Cell · doi:10.1016/j.cell.2004.06.006 · Cited by 3,856 · see citing works
Cano, A., Pérez‐Moreno, M., Rodrigo, I., Locascio, A., Blanco, M. J., Barrio, M. G. D., Portillo, F., & Nieto, M. A. (2000) · Nature Cell Biology · doi:10.1038/35000025 · Cited by 3,672 · see citing works
Biomarkers for epithelial-mesenchymal transitions
Zeisberg, M., & Neilson, E. G. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36183 · Cited by 2,299 · see citing works
The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.
Comijn, J., Berx, G., Vermassen, P., Verschueren, K., van Grunsven, L. V., Bruyneel, E., Mareel, M., Huylebroeck, D., & van Roy, F. (2001) · Molecules and Cells · doi:10.1016/s1097-2765(01)00260-x · Cited by 1,464 · see citing works
The cell-cell adhesion molecule E-cadherin
Roy, F. M. V., & Berx, G. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8281-1 · Cited by 1,330 · see citing works
Bolós, V., Peinado, H., Pérez‐Moreno, M., Fraga, M. F., Esteller, M., & Cano, A. (2002) · Journal of Cell Science · doi:10.1242/jcs.00224 · Cited by 1,100 · see citing works
Voulgari, A., & Pintzas, A. (2009) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2009.03.002 · Cited by 672 · see citing works
E-cadherin–integrin crosstalk in cancer invasion and metastasis
Canel, M., Serrels, A., Frame, M. C., & Brunton, V. G. (2013) · Journal of Cell Science · doi:10.1242/jcs.100115 · Cited by 624 · see citing works
T-Box Genes in Vertebrate Development
Naiche, L. A., Harrelson, Z., Kelly, R. G., & Papaioannou, V. E. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.073003.105925 · Cited by 426 · see citing works
Epithelial–mesenchymal transition and tumour invasion
Guarino, M. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.07.011 · Cited by 369 · see citing works
Jacobs, J. J. L., Keblusek, P., Robanus-Maandag, E., Kristel, P., Lingbeek, M., Nederlof, P. M., van Welsem, T., van de Vijver, M. J., Koh, E. Y., Daley, G. Q., et al. (2000) · Nature Genetics · doi:10.1038/81583 · Cited by 368 · see citing works
Habets, P. E. M. H., Moorman, A. F. M., Clout, D. E. W., van ROON, M. A., Lingbeek, M., van Lohuizen, M., Campione, M., & Christoffels, V. M. (2002) · Genes & Development · doi:10.1101/gad.222902 · Cited by 366 · see citing works
Tanaka, M., Katayama, F., Katô, H., Tanaka, H., Wang, J., Qiao, Y., & Inoue, M. (2011) · Journal of Epidemiology · doi:10.2188/jea.je20100190 · Cited by 304 · see citing works
Brachyury-Related Transcription Factor Tbx2 and Repression of the Melanocyte-Specific TRP-1 Promoter
Carreira, S., Dexter, T. J., Yavuzer, U., Easty, D. J., & Goding, C. R. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.9.5099 · Cited by 173 · see citing works
Lingbeek, M. E., Jacobs, J. J. L., & van Lohuizen, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200403200 · Cited by 160 · see citing works
Renard, C.-A., Labalette, C., Armengol, C., Cougot, D., Wei, Y., Cairo, S., Pineau, P., Neuveut, C., de Reyniès, A., Dejean, A., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2344 · Cited by 157 · see citing works
Tbx3 Represses E-Cadherin Expression and Enhances Melanoma Invasiveness
Rodriguez, M., Aladowicz, E., Lanfrancone, L., & Goding, C. R. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0301 · Cited by 157 · see citing works
Brummelkamp, T. R., Kortlever, R. M., Lingbeek, M., Trettel, F., MacDonald, M. E., van Lohuizen, M., & Bernards, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110492200 · Cited by 154 · see citing works
Zhai, X., Zhu, H., Wang, W., Zhang, S., Zhang, Y., & Mao, G. (2014) · Medical Oncology · doi:10.1007/s12032-014-0970-z · Cited by 123 · see citing works
Coll, M., Seidman, J. G., & Müller, C. W. (2002) · Structure · doi:10.1016/s0969-2126(02)00722-0 · Cited by 121 · see citing works
Vervoort, S. J., Lourenço, A. R., van Boxtel, R., & Coffer, P. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053238 · Cited by 93 · see citing works
Tu, K., Zheng, X. M., Dou, C., Li, C., Yang, W., Yao, Y., & Liu, Q. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151120486 · Cited by 70 · see citing works
The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway
Li, J., Weinberg, M. S., Zerbini, L., & Prince, S. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e13-05-0273 · Cited by 56 · see citing works
Boyd, S. C., Mijatov, B., Pupo, G. M., Tran, S. L., Gowrishankar, K., Shaw, H. M., Goding, C. R., Scolyer, R. A., Mann, G. J., Kefford, R. F., et al. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.421 · Cited by 53 · see citing works
Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma
Burgucu, D., Guney, K., Sahinturk, D., Ozbudak, I. H., Ozel, D., Ozbilim, G., & Yavuzer, U. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-481 · Cited by 52 · see citing works
HCC—subtypes, stratification and sorafenib
Gores, G. J. (2014) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2014.157 · Cited by 46 · see citing works
Du, H. F., Ou, L. P., Yang, X., Song, X. D., Fan, Y. R., Tan, B., Luo, C. L., & Wu, X. H. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2013.11.015 · Cited by 43 · see citing works
Miao, Z.-F., Liu, X.-Y., Xu, H.-M., Wang, Z.-N., Zhao, T.-T., Song, Y.-X., Xing, Y.-N., Huang, J.-Y., Zhang, J.-Y., Xu, H., et al. (2016) · Virchows Archiv · doi:10.1007/s00428-016-2007-9 · Cited by 20 · see citing works
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The roles and regulation of TBX3 in development and disease
Khan, S. F., Damerell, V., Omar, R., Du Toit, M., Khan, M., Maranyane, H. M., Mlaza, M., Bleloch, J., Bellis, C., Sahm, B. D. B., et al. (2020) · Gene · doi:10.1016/j.gene.2019.144223 · Cited by 99 · see citing works
“Indeed, uncontrolled cell proliferation and the bypass of senescence and apoptosis are early events in oncogenesis, and TBX3 has been shown to impact these processes as well as to promote tumour formation, angiogenesis and metastasis (Dong et al., 2018b, 2018a; Feng et al., 2018; Krstic et al., 2019; Wang, 2018; Willm…”
BackgroundResultBravo González-Blas, C., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-023-01316-4 · Cited by 85 · see citing works
“Human HepG2 cells express Tbx3 and can therefore be used as a model to test the effect of mutating TBX3 sites in hepatocyte enhancer sequences 45 .”
Lee, Y.-J., Park, J., & Oh, S. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.11.104 · 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
“To verify that repression of E2f7 and E2f8 by TBX3 occurs on the regulatory sequences of these genes, we employed a luciferase reporter assay in human hepatoblastoma HepG2 cells, which express TBX3 at high levels (32).”
MethodJi, X., Chen, X., Zhang, B., Xie, M., Zhang, T., Luo, X., Liu, D., Feng, Y., Wang, Y., Sun, M., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02249-2 · Cited by 21 · see citing works
Context-dependent T-BOX transcription factor family: from biology to targeted therapy
Li, S., Luo, X., Sun, M., Wang, Y., Zhang, Z., Jiang, J., Hu, D., Zhang, J., Wu, Z., Wang, Y., et al. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01719-2 · Cited by 17 · see citing works
Self-citationLi, M., Li, T., Jin, T., Chen, Y., Cheng, L., Liang, Q., Yan, S., Li, T., Ran, Q., & Chen, W. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08870-y · Cited by 9 · see citing works
Huang, Y., Zhu, H., Ji, X., Chen, Y., Zhang, Y., Huang, R., Xie, J., & Dong, P. (2019) · Oncology Letters · doi:10.3892/ol.2019.11089 · Cited by 9 · see citing works
Jauregi‐Miguel, A., Söderholm, S., Weiss, T., Nordin, A., Ghezzi, V., Brütsch, S. M., Pagella, P., van de Grift, Y. B. C., Zambanini, G., Ulisse, J., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2419691122 · Cited by 6 · see citing works
Enhancer grammar of liver cell types and hepatocyte zonation states
González-Blas, C. B., Matetovici, I., Hillen, H., Taskiran, I. I., Vandepoel, R., Christiaens, V., Sansores-García, L., Verboven, E., Hulselmans, G., Poovathingal, S., et al. (2022) · doi:10.1101/2022.12.08.519575 · Cited by 5 · see citing works
Zhuo, F., Li, J., Wang, Y., Li, M., Song, F.-F., Liu, Y.-L., & Tao, Z.-Y. (2022) · European Journal of Inflammation · doi:10.1177/1721727x221093056 · Cited by 3 · see citing works
Jin, 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
TBX3 promotes the epithelial mesenchymal transition of cervical cancer by upregulating ID1.
Yang, H., Sun, Y., Jia, X., Cai, Y., Zhao, X., & Li, N. (2023) · PubMed Central · Cited by 2 · see citing works
- Authors
- Feng, X., Yao, W., Zhang, Z., Yuan, F., Liang, L., Zhou, J., Liu, S., & Song, J.
- Affiliations
- Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Tianqiao District, Jinan, Shandong, P.R. China
- Shandong Center for Disease Control and Prevention (CN)
- Shandong University (CN)
- ORCID
- Venue
- Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics
- Publisher
- Tech Science Press
- Published
- 2018-07-05
- Volume
- 26
- Issue
- 6
- Pages
- 959-966
- ISSN
- 0965-0407 (ISSN-L)
- PMC
- PMC7844722
- OpenAlex
- W2781921089
- Cited by
- 13
- References
- 29
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 1 · 2019: 3
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2026-09-14)
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- TBX3, hepatocellular carcinoma, E-cadherin, epithelial-mesenchymal transition, tumor cell migration, tumor invasion, metastasis, prognostic factors, transcriptional repression, therapeutic target
- MeSH terms
- Cell Movement, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Neoplasm Invasiveness, Prognosis, Tumor Cells, Cultured, Biomarkers, Tumor, Antigens, CD, Cadherins, Gene Expression Regulation, Neoplastic, Survival Rate, Apoptosis, T-Box Domain Proteins, Cell Proliferation
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