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Tbx3 Is a Downstream Target of the Wnt/β-Catenin Pathway and a Critical Mediator of β-Catenin Survival Functions in Liver Cancer
Published version of a preprint
Abstract
Tbx3 encodes a transcriptional repressor that is important for diverse patterning events during development, and Tbx3 mutation in humans causes the ulnar-mammary syndrome. Here, we describe the identification of Tbx3 in array-based search for genes downstream Wnt/β-catenin that are implicated in liver tumorigenesis. Overexpression of Tbx3 is closely associated with the mutational status of β-catenin in murine liver tumors induced by Myc as well as in human hepatocellular carcinomas and hepatoblastomas. Moreover, Tbx3 transcription is activated by ectopic expression of β-catenin in mouse liver and in human tumor cell lines. Evidence that Tbx3 transcription is directly regulated by β-catenin is provided by chromatin immunoprecipitation and reporter assays. Although HepG2 cells stably transfected with Tbx3 display moderately enhanced growth rate, the dominant negative mutant Tbx3-Y149S drastically inhibits hepatoma cell growth in vitro and in vivo. Moreover, small interfering RNAs (siRNA) directed against Tbx3 inhibit anchorage-independent growth of liver and colon carcinoma cells. We further show that inhibition of Tbx3 expression by specific siRNAs blocks β-catenin–mediated cell survival and renders cells sensitive to doxorubicin-induced apoptosis. Conversely, ectopic expression of Tbx3 inhibits apoptosis induced by β-catenin depletion. Marked overexpression of Tbx3 in a subset of hepatoblastomas is associated with chemotherapy-resistant phenotype and unfavorable patient outcome. These results reveal an unsuspected role of Tbx3 as a mediator of β-catenin activities on cell proliferation and survival and as an important player in liver tumorigenesis. [Cancer Res 2007;67(3):901–10]
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Citations
Cites
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Irizarry, R. A. (2003) · Biostatistics · doi:10.1093/biostatistics/4.2.249 · Cited by 10,603
Caught up in a Wnt storm: Wnt signaling in cancer
Giles, R. H., van Es, J. H., & Clevers, H. (2003) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(03)00005-2 · Cited by 1,482 · cited 1×
“The Wnt/Wingless pathway plays a pivotal role in embryonic development and adult homeostasis by regulating cell fate, proliferation, and differentiation, and it is aberrantly reactivated in various human cancers ( 1 ).”
BackgroundMolecular pathogenesis of human hepatocellular carcinoma
Thorgeirsson, S. S., & Grisham, J. W. (2002) · Nature Genetics · doi:10.1038/ng0802-339 · Cited by 1,456
Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas
Coste, A. D. L., Romagnolo, B., Billuart, P., Renard, C.-A., Buendia, M., Soubrane, O., Fabrè, M., Chelly, J., Beldjord, C., Kahn, A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.15.8847 · Cited by 1,157
Self-citationLaurent‐Puig, P., Legoix, P., Bluteau, O., Belghiti, J., Franco, D., Binot, F., Monges, G. M., Thomas, G. D., Bioulac‐Sage, P., & Zucman‐Rossi, J. (2001) · Gastroenterology · doi:10.1053/gast.2001.24798 · Cited by 582 · cited 2×
“It suggests that the Wnt/h-catenin pathway was activated through other means, such as overexpression of Frizzled-7 or loss-of-function mutations of Axin ( 9 ).”
BackgroundApc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver
Benhamouche, S., Decaens, T., Godard, C., Chambrey, R., Rickman, D. S., Moinard, C., Vasseur-Cognet, M., Kuo, C. J., Kahn, A., Perret, C., et al. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.03.015 · Cited by 543
Self-citationMutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome
Bamshad, M., Lin, R. C., Law, D. J., Watkins, W. S., Krakowiak, P. A., Moore, M. E., Franceschini, P., Lala, R., Holmes, L. B., Gebuhr, T. C., et al. (1997) · Nature Genetics · doi:10.1038/ng0797-311 · Cited by 540 · cited 2×
“In particular, Tbx3 is expressed in the mesenchyme at the limb bud margins and in the mammary buds, correlating with defects in anteroposterior patterning and mammary gland induction in Tbx3-deficient mice and in UMS patients (22, 23 , 38).”
BackgroundT (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specificationPreprint
Yamaguchi, T. P., Takada, S., Yoshikawa, Y., Wu, N., & McMahon, A. P. (1999) · Genes & Development · doi:10.1101/gad.13.24.3185 · Cited by 527
Lee, J.-S., Chu, I.-S., Mikaelyan, A., Calvisi, D., Heo, J., Reddy, J., & Thorgeirsson, S. (2004) · Nature Genetics · doi:10.1038/ng1481 · Cited by 472 · cited 1×
“We show that Tbx3 expression is activated by Wnt/h-catenin signaling in murine as well as in human liver tumors, confirming the value of mouse models to study molecular events that occur in HCC ( 34 ).”
BackgroundNew targets of β-catenin signaling in the liver are involved in the glutamine metabolism
Cadoret, A., Ovejero, C., Terris, B., Souil, E., Lévy, L., Lamers, W. H., Kitajewski, J., Kahn, A., & Perret, C. (2002) · Oncogene · doi:10.1038/sj.onc.1206118 · Cited by 412
Self-citationJacobs, 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
Genetics of hepatocellular carcinoma
Buendia, M. A. (2000) · Seminars in Cancer Biology · doi:10.1006/scbi.2000.0319 · Cited by 331
Self-citationChamorro, M., Schwartz, D. R., Vonica, A., Brivanlou, A. H., Cho, K. R., & VARMUS, H. E. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600460 · Cited by 300 · cited 1×
“Overexpression of Tbx3 is not restricted to liver cancer because it has been described in breast and ovarian cancer (30, 48) and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/hcatenin pathway ( 49 ).”
BackgroundDavenport, T. G., Jerome-Majewska, L. A., & Papaioannou, V. E. (2003) · Development · doi:10.1242/dev.00431 · Cited by 295 · cited 2×
“Tbx3 is notably implicated in heart, limb, and posterior digit specification and in mammary gland development (21, 22 ).”
BackgroundSekine, S., Lan, B. Y., Bedolli, M., Feng, S., & Hebrok, M. (2006) · Hepatology · doi:10.1002/hep.21131 · Cited by 295
Verma, U. N., Surabhi, R. M., Schmaltieg, A., Becerra, C. R., & Gaynor, R. B. (2003) · PubMed · Cited by 294
Orford, K. W., Orford, C. C., & Byers, S. W. (1999) · The Journal of Cell Biology · doi:10.1083/jcb.146.4.855 · Cited by 276
Pritchard, J., Brown, J. M., Shafford, E., et al. (2000) · Journal of Clinical Oncology · doi:10.1200/jco.2000.18.22.3819 · Cited by 270
Isl1Cre reveals a common Bmp pathway in heart and limb development
Yang, L., Cai, C.-L., Lin, L., Qyang, Y., Chung, C., Monteiro, R. M., Mummery, C. L., Fishman, G. I., Cogen, A., & Evans, S. (2006) · Development · doi:10.1242/dev.02322 · Cited by 267 · cited 1×
“Notably, it has been shown that Tbx3 is a direct target of BMP Smads ( 43 ).”
BackgroundFunctional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma
Merle, P., de la Monte, S., Kim, M., Herrmann, M., Tanaka, S., Von Dem Bussche, A., Kew, M. C., Trepo, C., & Wands, J. R. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.07.009 · Cited by 249
Monga, S. P., Monga, H. K., Tan, X., Mulé, K., Pediaditakis, P., & Michalopoulos, G. K. (2003) · Gastroenterology · doi:10.1053/gast.2003.50000 · Cited by 221 · cited 8×
“www.aacrjournals.org 905 Cancer Res 2007; 67: ( 3 ).”
BackgroundMethodInfluentialEpidermal Growth Factor Receptor: A Novel Target of the Wnt/β-Catenin Pathway in Liver
Tan, X., Apte, U. M., Micsenyi, A., Kotsagrelos, E., Luo, J.-H., Ranganathan, S., Monga, D. K., Bell, A. W., Michalopoulos, G. K., & Monga, S. P. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.04.013 · Cited by 219
Aronson, D. C., Schnater, J. M., Staalman, C. R., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.07.145 · Cited by 218
p19ARF directly and differentially controls the functions of c-Myc independently of p53
Qi, Y., Gregory, M. A., Li, Z., Brousal, J. P., West, K. A., & Hann, S. (2004) · Nature · doi:10.1038/nature02958 · Cited by 214 · cited 1×
“These effects can be explained by transcriptional repression of the ARF tumor suppressor gene by Tbx3, leading in turn to the down-regulation of p53 and the activation of Myc-induced proliferation and transformation, but not Myc-induced apoptosis (26, 45 ).”
BackgroundWnt signaling promotes oncogenic transformation by inhibiting c-Myc–induced apoptosis
You, Z., Saims, D., Chen, S., Zhang, Z., Guttridge, D. C., Guan, K., MacDougald, O. A., Brown, A. M. C., Evan, G. I., Kitajewski, J., et al. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200201110 · Cited by 211 · cited 1×
“Wnt/hcatenin signaling is known to protect cells from Myc-induced apoptosis, thereby facilitating transformation ( 44 ).”
BackgroundControl of the Gene optomotor-blind in Drosophila Wing Development by decapentaplegic and wingless
Grimm, S., & Pflugfelder, G. O. (1996) · Science · doi:10.1126/science.271.5255.1601 · Cited by 205
β-Catenin is temporally regulated during normal liver development☆
Micsenyi, A., Tan, X., Sneddon, T., Luo, J., Michalopoulos, G. K., & Monga, S. P. (2004) · Gastroenterology · doi:10.1053/j.gastro.2003.12.047 · Cited by 191
Activation of β-catenin in epithelial and mesenchymal hepatoblastomas
Yu, W., Fabrè, M., Branchereau, S., Gauthier, F., Perilongo, G., & Buendia, M. (2000) · Oncogene · doi:10.1038/sj.onc.1203356 · Cited by 176 · cited 1×
“The expression vector for dominant stable h-catenin T41A was described previously ( 28 ).”
BackgroundSelf-citationHepatomegaly in transgenic mice expressing an oncogenic form of beta-catenin.
Cadoret, A., Ovejero, C., Saadi-Kheddouci, S., Souil, E., Fabrè, M., Romagnolo, B., Kahn, A., & Perret, C. (2001) · PubMed · Cited by 169
Self-citationOncogenic role of the frizzled-7/β-catenin pathway in hepatocellular carcinoma
Merle, P., Kim, M., Herrmann, M., Gupte, A. R., Lefrançois, L., Califano, S., TREPO, C. G., Tanaka, S., Vitvitski, L., de la Monte, S. M., et al. (2005) · Journal of Hepatology · doi:10.1016/j.jhep.2005.05.018 · Cited by 158
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 · cited 3×
“target of Tbx2/Tbx3 has linked these transcriptional repressors to the control of cell cycle and senescence and to the antiproliferative response delivered by the ARF-Mdm2-p53 pathway in tumorigenesis (25, 26 ).”
BackgroundMethodInfluentialTbx Genes Specify Posterior Digit Identity through Shh and BMP Signaling
Suzuki, T., Takeuchi, J., Koshiba-Takeuchi, K., & Ogura, T. (2004) · Developmental Cell · doi:10.1016/s1534-5807(03)00401-5 · Cited by 148 · cited 1×
“Tbx3 is notably implicated in heart, limb, and posterior digit specification and in mammary gland development ( 21 , 22).”
BackgroundFan, W., Huang, X., Chen, C., Gray, J., & Huang, T. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0615 · Cited by 136 · cited 3×
“Enhanced expression of Tbx3 was confirmed by Northern and Western blotting (Fig. 1). The mRNA levels of Tbx3 and the longer isoform Tbx3 + 2a ( 30 ) were increased 2- to 10-fold in tumors with mutant h-catenin compared with tumors with wt h-catenin and normal liver (Fig. 1A).”
BackgroundInfluentialTranscriptional Activation of Interleukin-8 by β-Catenin-Tcf4
Lévy, L., Neuveut, C., Renard, C.-A., Charneau, P., Branchereau, S., Gauthier, F., Nhieu, J. T. V., Cherqui, D., Petit-Bertron, A.-F., Mathieu-Mahul, D., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207418200 · Cited by 133
Self-citationSuksaweang, S., Lin, C., Jiang, T., Hughes, M. W., Widelitz, R. B., & Chuong, C. (2003) · Developmental Biology · doi:10.1016/j.ydbio.2003.10.010 · Cited by 127
Eblaghie, M. C., Song, S., Kim, J., Akita, K., Tickle, C., & Jung, H. (2004) · Journal of Anatomy · doi:10.1111/j.0021-8782.2004.00309.x · Cited by 121 · cited 1×
“February 1, 2007 908 www.aacrjournals.org effect of Wnt and fibroblast growth factor signals in mammary gland initiation ( 39 ).”
BackgroundHe, M.-L., Wen, L., Campbell, C. E., Wu, J. Y., & Rao, Y. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.18.10212 · Cited by 120 · cited 1×
“Tbx2/Tbx3 contain a conserved transcription-repression domain and can repress basal and activated transcription ( 24 ).”
BackgroundLi, Y., Zhang, H., Choi, S. C., Litingtung, Y., & Chiang, C. C. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.03.009 · Cited by 108
Carlson, H., Ota, S., Song, Y., Chen, Y., & Hurlin, P. J. (2002) · Oncogene · doi:10.1038/sj.onc.1205476 · Cited by 102
A -catenin-dependent pathway regulates expression of cytochrome P450 isoforms in mouse liver tumors
Loeppen, S. (2004) · Carcinogenesis · doi:10.1093/carcin/bgh298 · Cited by 102 · cited 1×
“In these six cases like in the mutant h-catenin group, other known targets of h-catenin were overexpressed, including GS (Supplementary Fig. S1), pancreatitisassociated protein, regenerating islet–derived-1a, neuronal cell adhesion molecule, bone morphogenic protein (BMP) 4, and CYP2E1 ( 15 , 17).”
BackgroundCalvisi, D. F., Factor, V. M., Loi, R., & Thorgeirsson, S. S. (2001) · PubMed · Cited by 93
Cavard, C., Terris, B., Grimber, G., Christa, L., Audard, V., Radenen, B., Simon, M. I., Renard, C. B., Buendia, M., & Perret, C. (2005) · Oncogene · doi:10.1038/sj.onc.1208860 · Cited by 93
Self-citationBehind the Official Optimism, Flawed Projections
Glanz, J. (1996) · Science · doi:10.1126/science.274.5293.1601 · Cited by 90
Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients
Lomnytska, M., Dubrovska, A., Hellman, U., Volodko, N., & Souchelnytskyi, S. (2006) · International Journal of Cancer · doi:10.1002/ijc.21332 · Cited by 83 · cited 1×
“Overexpression of Tbx3 is not restricted to liver cancer because it has been described in breast and ovarian cancer (30, 48 ) and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/hcatenin pathway (49).”
BackgroundRegulation of Tbx3 expression by anteroposterior signalling in vertebrate limb development.
Tümpel, S., Sanz-Ezquerro, J., Isaac, A., Eblaghie, M. C., Dobson, J., & Tickle, C. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0762 · Cited by 76
Gross, J. M., Peterson, R. E., Wu, S.-Y., & McClay, D. R. (2003) · Development · doi:10.1242/dev.00409 · Cited by 65
Étiemble, J., Degott, C., Renard, C. A., et al. (1994) · PubMed · Cited by 52
Self-citationRenard, C.-A., Fourel, G., Bralet, M., Degott, C., Coste, A. D. L., Perret, C., Tiollais, P., & Buendia, M. A. (2000) · Oncogene · doi:10.1038/sj.onc.1203617 · Cited by 47
Self-citationPML interacts with Myc, and Myc target gene expression is altered in PML-null fibroblasts
Cairo, S., Falco, F. D., Pizzo, M., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1208338 · Cited by 41
Self-citationTakabatake, Y., Takabatake, T., Sasagawa, S., & Takeshima, K. (2002) · Development Growth & Differentiation · doi:10.1046/j.1440-169x.2002.00640.x · Cited by 40
Prognostic impact of molecular genetic alterations in hepatoblastoma
von Schweinitz, D., Kraus, J. A., Albrecht, S., et al. (2002) · Medical and Pediatric Oncology · doi:10.1002/mpo.1280 · Cited by 33
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BackgroundSelf-citationIdentification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis
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“and that TBX3 is a direct downstream target of the Wnt–β-catenin pathwa”
BackgroundKong, L., Pokatayev, V., Lefkovith, A. J., Carter, G. T., Creasey, E. A., Krishna, C., Subramanian, S., Kochar, B. D., Ashenberg, O., Lau, H., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.01.002 · Cited by 291
Metadata
- Authors
- Renard, C.-A., Labalette, C., Armengol, C., Cougot, D., Wei, Y., Cairo, S., Pineau, P., Neuveut, C., de Reyniès, A., Dejean, A., Perret, C., & Buendia, M.-A.
- Affiliations
- 1Institut National de la Sante et de la Recherche Medicale, U579;
- Inserm (FR)
- 4Ligue Nationale contre le Cancer;
- ORCID
- Venue
- Cancer Research
- Published
- 2007-02-01
- Volume
- 67
- Issue
- 3
- Pages
- 901-910
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2142575284
- Cited by
- 157
- References
- 51
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 5 · 2020: 10 · 2019: 7 · 2018: 10 · 2017: 7 · 2016: 8 · 2015: 8 · 2014: 12 · 2013: 14 · 2012: 12
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- HAL (Le Centre pour la Communication Scientifique Directe) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- TBX3, Wnt/β-catenin signaling, hepatocarcinogenesis, hepatocellular carcinoma, hepatoblastoma, transcriptional repression, doxorubicin sensitivity, apoptosis, chemoresistance, cell proliferation, ulnar-mammary syndrome
- MeSH terms
- Animals, Cell Adhesion, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Liver Neoplasms, Experimental, Mice, Transgenic, Mutation, Promoter Regions, Genetic, Transcription, Genetic, Transfection, Genes, myc, Apoptosis, T-Box Domain Proteins, RNA, Small Interfering, Cell Line, Tumor, Cell Growth Processes, Wnt Proteins, beta Catenin, Mice, TCF Transcription Factors
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