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Tbx3 Is a Downstream Target of the Wnt/ß-Catenin Pathway and a Critical Mediator of ß-Catenin Survival Functions in Liver Cancer

¹ Institut National de la Sante et de la Recherche Medicale, U579; ² Oncogenesis and Molecular Virology Unit and ³ Nuclear Organization and Oncogenesis Unit, Institut Pasteur; ⁴ Ligue Nationale contre le Cancer; ⁵ Département Génétique, Développement et Pathologie Moléculaire, Institut Cochin; and ⁶ Institut National de la Sante et de la Recherche Medicale, U567, Paris, France

Requests for reprints: Marie-Annick Buendia, Oncogenesis and Molecular Virology Unit, Institut National de la Sante et de la Recherche Medicale U579, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris, France. Phone: 33-145-688-866; Fax: 33-145-688-943; E-mail: mbuendia{at}pasteur.fr.

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/ß-catenin that are implicated in liver tumorigenesis. Overexpression of Tbx3 is closely associated with the mutational status of ß-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 ß-catenin in mouse liver and in human tumor cell lines. Evidence that Tbx3 transcription is directly regulated by ß-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 ß-catenin–mediated cell survival and renders cells sensitive to doxorubicin-induced apoptosis. Conversely, ectopic expression of Tbx3 inhibits apoptosis induced by ß-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 ß-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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