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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

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/beta-catenin that are implicated in liver tumorigenesis. Overexpression of Tbx3 is closely associated with the mutational status of beta-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 beta-catenin in mouse liver and in human tumor cell lines. Evidence that Tbx3 transcription is directly regulated by beta-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 beta-catenin-mediated cell survival and renders cells sensitive to doxorubicin-induced apoptosis. Conversely, ectopic expression of Tbx3 inhibits apoptosis induced by beta-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 beta-catenin activities on cell proliferation and survival and as an important player in liver tumorigenesis.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02870434
Contributor : Pascal Pineau <>
Submitted on : Tuesday, June 16, 2020 - 4:45:26 PM
Last modification on : Wednesday, September 16, 2020 - 5:52:12 PM

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Claire-Angélique Renard, Charlotte Labalette, Carolina Armengol, Delphine Cougot, Yu Wei, et al.. Tbx3 Is a Downstream Target of the Wnt/β-Catenin Pathway and a Critical Mediator of β-Catenin Survival Functions in Liver Cancer. Cancer Research, American Association for Cancer Research, 2007, 67 (3), pp.901-910. ⟨10.1158/0008-5472.CAN-06-2344⟩. ⟨pasteur-02870434⟩

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