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

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Tbx3 Is a Downstream Target of the Wnt/B-Catenin Pathway and a Critical Mediator of B-Catenin Survival Functions in Liver Cancer Research Article Tbx3 Is a Downstream Target of the Wnt/B-Catenin Pathway and a Critical Mediator of B-Catenin Survival Functions in Liver Cancer Claire-Ange´lique Renard,1,2 Charlotte Labalette,1,2 Carolina Armengol,1,2 Delphine Cougot,1,2 Yu Wei,1,2 Stefano Cairo,1,2 Pascal Pineau,1,3 Christine Neuveut,1,2 Aure´lien de Reynie`s,4 Anne Dejean,1,3 Christine Perret,5,6 and Marie-Annick Buendia1,2 1Institut National de la Sante et de la Recherche Medicale, U579; 2Oncogenesis and Molecular Virology Unit and 3Nuclear Organization and Oncogenesis Unit, Institut Pasteur; 4Ligue Nationale contre le Cancer; 5De´partementGe´ne´tique,De´veloppementet Pathologie Mole´culaire, Institut Cochin; and 6Institut National de la Sante et de la Recherche Medicale, U567, Paris, France Abstract interacts with DNA-binding factors of the T-cell factor/lymphoid enhancer factor (Tcf/Lef) family to promote transcription of Wnt Tbx3 encodes a transcriptional repressor that is important for diverse patterning events during development, and Tbx3 target genes. Depending on cell context, the selective expression of mutation in humans causes the ulnar-mammary syndrome. distinct sets of Wnt-responsive genes is strictly controlled by the interplay of signaling pathways. Increasing numbers of candidate Here, we describe the identification of Tbx3 in array-based h search for genes downstream Wnt/B-catenin that are impli- -catenin targets include cell cycle and growth regulators and proteins involved in cell-matrix interactions, migration and cated in liver tumorigenesis. Overexpression of Tbx3 is closely 7 B invasion, and in the regulation of the Wnt pathway. associated with the mutational status of -catenin in murine h liver tumors induced by Myc as well as in human hepatocel- Recent studies have outlined the importance of Wnt/ -catenin lular carcinomas and hepatoblastomas. Moreover, Tbx3 signaling in regulating liver cell proliferation during development transcription is activated by ectopic expression of B-catenin (2–4) and in governing essential functions in the adult liver (5–7). in mouse liver and in human tumor cell lines. Evidence that Moreover, aberrant reactivation of Wnt signaling is a predominant B mechanism implicated in liver tumorigenesis. Mutations of the Tbx3 transcription is directly regulated by -catenin is h provided by chromatin immunoprecipitation and reporter -catenin and Axin genes leading to constitutive activation of h-catenin have been identified in hepatocellular carcinoma (HCC) assays. Although HepG2 cells stably transfected with Tbx3 display moderately enhanced growth rate, the dominant and hepatoblastoma, and frequent overexpression of the Wnt negative mutant Tbx3-Y149S drastically inhibits hepatoma receptor Frizzled-7 is a major early event in hepatocarcinogenesis in vitro in vivo (refs. 8–11; for reviews, see refs. 12, 13). Animal models have been cell growth and . Moreover, small interfering h RNAs (siRNA) directed against Tbx3 inhibit anchorage- instrumental in allowing the identification of -catenin target independent growth of liver and colon carcinoma cells. We genes in nondiseased or tumorous liver, including liver-specific further show that inhibition of Tbx3 expression by specific enzymes involved in glutamine and nitrogen metabolism, such as siRNAs blocks B-catenin–mediated cell survival and renders glutamine synthetase (GS), ornithine aminotransferase, the gluta- cells sensitive to doxorubicin-induced apoptosis. Conversely, mate transporter (GLT-1), and the cytochrome P450 enzymes ectopic expression of Tbx3 inhibits apoptosis induced by CYP1A2 and CYP2E1 (5, 6, 14–17). However, c-myc has not been found thus far to be regulated by h-catenin in the liver context, and B-catenin depletion. Marked overexpression of Tbx3 in a subset of hepatoblastomas is associated with chemotherapy- the oncogenic program triggered by Wnt signaling in hepatocarci- nogenesis remains largely unknown. resistant phenotype and unfavorable patient outcome. These Myc results reveal an unsuspected role of Tbx3 as a mediator of We have shown previously that transgenic mice carrying a B-catenin activities on cell proliferation and survival and as oncogene controlled by woodchuck hepatitis virus (WHV) regu- latory sequences were highly predisposed to liver cancer (18, 19). an important player in liver tumorigenesis. [Cancer Res h 2007;67(3):901–10] Activating mutations of -catenin were found at significant rates in these HCCs, as for other Myc transgenic strains, suggesting that the survival functions of h-catenin might rescue tumor cells from Introduction Myc-induced apoptosis (8, 19, 20). Consistent with this notion, The Wnt/Wingless pathway plays a pivotal role in embryonic inactivation of p53 was found to represent an alternative oncogenic development and adult homeostasis by regulating cell fate, mechanism (9, 19). To explore downstream genetic programs proliferation, and differentiation, and it is aberrantly reactivated activated by Wnt/h-catenin signaling in liver cancer, we employed in various human cancers (1). Mutations in adenomatous polyposis microarray profiling and found that the T-box protein 3 (Tbx3) was coli, Axin, and h-catenin genes that mimic Wnt activation result in specifically activated in murine tumors carrying mutant h-catenin. the stabilization of h-catenin, which then moves to the nucleus and The closely related genes TBX2 and TBX3 are members of the T-box gene family that play an important role in patterning events during development. Tbx3 is notably implicated in heart, limb, Note: Supplementary data for this article are available at Cancer Research Online and posterior digit specification and in mammary gland develop- (http://cancerres.aacrjournals.org/). Requests for reprints: Marie-Annick Buendia, Oncogenesis and Molecular ment (21, 22). In humans, Tbx3 mutations are responsible for the 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: [email protected]. I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-06-2344 7 http://www.stanford.edu/~rnusse/pathways/targets.html. www.aacrjournals.org 901 Cancer Res 2007; 67: (3). February 1, 2007 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2007 American Association for Cancer Research. Cancer Research ulnar-mammary syndrome (UMS), an autosomal dominant disor- Total RNA was extracted from each sample using the RNeasy Kit der characterized by upper limb deficiencies and apocrine/ (Qiagen) and treated with RNase-free DNase (Ambion). mammary gland hypoplasia (23). Tbx2/Tbx3 contain a conserved Oligonucleotide microarray and statistical analysis. Fifty-five human transcription-repression domain and can repress basal and HCCs, 24 hepatoblastomas, and 9 pools of nontumorous livers (5 from adults and 4 from children) were selected on the basis of high RNA quality as activated transcription (24). Identification of p14ARF as a direct determined with the Agilent 2100 bioanalyzer (Agilent Technologies, Palo target of Tbx2/Tbx3 has linked these transcriptional repressors Alto, CA). Raw feature data from Affymetrix HG-U133A GeneChip micro- to the control of cell cycle and senescence and to the antipro- arrays were obtained for these samples. All samples were processed using the liferative response delivered by the ARF-Mdm2-p53 pathway in one-cycle target labeling protocol.8 We analyzed the data using the tumorigenesis (25, 26). R system software (v2.2.1), GeneSpring GX 7.3, and BRB ArrayTools (v3.3.1). In this study, we showed that the expression of Tbx3, but not Tbx2, Raw feature data were normalized using the Robust Multi-array method was induced by mutant h-catenin in different systems, including (R package affy, v1.4.32; ref. 27), which yielded log2 intensity expression normal murine liver, murine and human liver tumors, and human summary values for each of the 22,283 probe sets. Each set (HCC and carcinoma cell lines. We cloned the TBX3 promoter and used a hepatoblastoma) was normalized independently. Additional statistical anal- combination of chromatin immunoprecipitation (ChIP) and report- yses were done with SPSS 11.0 package (SPSS, Inc., Chicago, IL). Comparison between groups was done using the Fisher’s exact test. Probability of er assays that led to identify Tbx3 as a direct transcriptional target of h overall survival was determined using the Kaplan-Meier analysis and the log- the -catenin/Tcf complex. We also showed that Tbx3 plays a crucial rank and Breslow tests. Follow-up was closed at the time of death or last visit. role in cell proliferation and survival. Inhibition of Tbx3 expression Plasmids. The reporter plasmid L-Tbx3-Luc carrying the TBX3 promoter by RNA interference dramatically reduced anchorage-independent was generated by PCR amplification of human genomic DNA sequences growth and abolished h-catenin protection over doxorubicin- (University of California–Santa CruzGenome Bioinformatics Site) extend- induced apoptosis in tumor cells. Finally, we propose that strong ing 2,226 bp upstream and 619 bp downstream of the transcriptional start overexpression of Tbx3 contributes to the chemotherapy-resistant site of the human TBX3 gene (GenBank accession number NM_016569). We phenotype of a subset of hepatoblastomas. used the following primers: L-Tbx3F, 5¶-CTAGCTAGCGAAACCCTGCAGT- GACTTCCG-3¶; and L-Tbx3R, 5¶-GGAAGATCTGCTCGAAATAGACACTC- CAGC-3¶. The PCR product was cloned into pGL3-Basic
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