Oncogenesis and Molecular Virology - INSERM U579  

  HEADBUENDIA Marie Annick / mbuendia@pasteur.fr
  MEMBERSNEUVEUT Christine / WEI Yu / ARMENGOL Carolina / BENHENDA Shirine / CAIRO Stefano / COUGOT Delphine / NOUET Yann / LEVILLAYER Florence / DA Louise Marie

  Annual Report

The team’s research focuses on the molecular pathogenesis of liver cancer, with particular emphasis on the role of hepatitis B virus (HBV) and the oncogenic activation of Wnt/ß-catenin signaling.

Chronic HBV infection is a major risk factor for the development of liver cancer, one of the commonest killer tumors in humans. Our recent work aims at defining new virus-cell interactions involved in the viral life cycle and the pathogenesis of HBV.

Cellular partners of the viral protein HBx in viral replication and oncogenesis

The HBV-encoded HBx oncoprotein is a multi-functional regulator of transcription and signal transduction. HBx activity is mandatory for HBV replication. We have found a direct, functional interaction of HBx with the acetyltransferases CBP/p300, which have a critical role in CREB-dependent transcription of cellular growth-related genes. The impact of this interaction on viral transcription from the HBV minichromosome, on viral replication and oncogenesis will be analyzed in vitro and in vivo. A new study has been launched to examine HBx interaction with the DDB1 subunit of the Cul4A ubiquitin E3 ligase complex. This complex might be subverted by HBx to benefit viral replication. Through crystal structure and proteomic

analysis, we will search for cellular substrates selectively targeted by the HBx/DDB1 complex.

Wnt/ß-catenin signaling in liver cancer

The Wnt/ß-catenin pathway plays a crucial role in development and it is aberrantly reactivated in human liver cancer by somatic mutations of ß-catenin. Our major goal is to identify cellular partners and target genes of ß-catenin that operate in liver oncogenesis. We have recently found that the FHL2 coactivator interacts with ß-catenin and is critically involved in the activation of Wnt-responsive genes such as cyclin D1. FHL2 interacts also with CBP/p300 and favors the acetylation of ß-catenin, which stabilizes the ß-catenin/Tcf complex on target promoters. Recent data in mouse embryo fibroblasts and in murine tumor models demonstrate that FHL2 deficiency impinges on cell cycle, cell immortalization and transformation, and strongly inhibits the onset of ß-catenin-related tumors.

Finally, using genome-wide approaches, we have identified a panel of Wnt target genes in human and murine liver tumors, notably Tbx3 that mediates the proliferative and anti-apoptotic effects of ß-catenin. In hepatoblastoma, the molecular signature of Wnt/ß-catenin signaling seems to be mainly imposed by liver environment but differs according to developmental stage and clinical subtype, providing new prognostic markers. Our main goal lies in basic research but our results have applications for cancer diagnosis, prognosis and therapy. To this aim, collaboration has been established with clinicians and pathologists involved in clinical trials.

Keywords: hepatitis B virus, HBx, hepatocellular carcinoma, hepatoblastoma, ▀-catenin, FHL2



Lévy, L., Y. Wei, C. Labalette, Y. Wu, C. A. Renard, M. A. Buendia, and C. Neuveut. 2004. Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction. Mol Cell Biol 8:3404-3414. PMID: 15060161

Labalette, C., C. A. Renard, C. Neuveut, M. A. Buendia, and Y. Wei. 2004. Interaction and funtional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin. Mol Cell Biol 24:10689-10702. PMID: 15572674

Cavard, C., B. Terris, G. Grimber, L. Christa, V. Audard, B. Radenen-Bussiere, M. T. Simon, C. A. Renard, M. A. Buendia, and C. Perret. 2006. Overexpression of regenerating Islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations. Oncogene 25:599-608. PMID: 16314847

Cougot, D., Y. Wu, S. Cairo, J. Caramel, C. A. Renard, L. Levy, M. A. Buendia, and C. Neuveut. 2007. The hepatitis B virus X protein functionally interacts with CBP/p300 in the regulation of CREB-mediated transcription. J Biol Chem 282:4277-4287. PMID: 17158882

Renard, C. A., C. Labalette, C. Armengol, D. Cougot, Y. Wei, S. Cairo, P. Pineau, A. De Reyniès, A. Dejean, C. Perret, and M. A. Buendia. 2007. Tbx3 is a downstream target of the Wnt/ß-catenin pathway and a critical mediator of ß-catenin survival functions in liver cancer. Cancer Res 67:901-910. PMID: 17283120

Activity Reports 2007 - Institut Pasteur
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