Oncogenesis and Molecular Virology - INSERM U579  


  HEADDr. BUENDIA Marie Annick / marie-annick.buendia@pasteur.fr
  MEMBERSDr. NEUVEUT Christine / Dr. WEI Yu / BENHENDA Shirine / CAIRO Stefano / COUGOT Delphine / DAHAN Jennifer / NOUET Yann / XIA Tian / LEVILLAYER Florence / DUROURE Karine / DENISOT Anne-Lyse / DA Louise Marie


  Annual Report

Our work seeks at better defining the molecular pathogenesis of liver cancer, with special focus on the role of hepatitis B virus (HBV) and oncogenic activation of Wnt/ß-catenin signaling. Chronic HBV infection is a major risk factor for the development of hepatocellular carcinoma, one of the commonest killer tumors in humans. Ongoing projects include the analysis of genetic alterations in HBV-associated tumors, in collaboration with the Institut Pasteur of Shangai, and the search for new virus-cell interactions involved in HBV replication and pathogenesis.

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 functional interaction of HBx with the acetyltransferases CBP/p300 and with the protein phosphatase PP1, which have critical roles in CREB-dependent transcription of cellular growth-related genes. The impact of these interactions on viral transcription from the HBV minichromosome, on viral replication and oncogenesis is 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 are searching for cellular substrates selectively targeted by the HBx/DDB1 complex.

Wnt/ß-catenin signaling in liver cancer

The Wnt/ß-catenin pathway is a key player during 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. Studies in mouse embryo fibroblasts demonstrate that the LIM-only protein FHL2 plays a pivotal role in cell cycle, cell immortalization and transformation. Our recent data in murine models outline FHL2 implication in liver regeneration and fibrosis and in Wnt-related intestinal tumorigenesis.

Finally, using genome-wide approaches, we have identified a panel of Wnt target genes in human and murine liver tumors. In hepatoblastoma, a pediatric tumor derived from hepatic progenitors, we have demonstrated that hepatic differentiation stage and clinical behavior are closely associated, and identified a molecular signature linked to Myc activation that can predict disease outcome. Current work aims at defining the oncogenic potential of Myc-driven microRNAs and their use as biomarkers in liver cancer. Our main goal lies in basic research but our results have applications for cancer diagnosis, prognosis and therapy.

Figure legend: Proposed model for the role of HBx on HBV transcription. In HBV replicating cells, HBx, CREB and its partners CBP/p300 are recruited onto the HBV cccDNA and activate transcription. HBx acts in part by inhibiting PP1 activity, thus allowing prolonged CREB phosphorylation and histone hyperacetylation.

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

buendia.jpg

Proposed model for the role of HBx on HBV transcription. In HBV replicating cells, HBx, CREB and its partners CBP/p300 are recruited onto the HBV cccDNA and activate transcription. HBx acts in part by inhibiting PP1 activity, thus allowing prolonged CREB phosphorylation and histone hyperacetylation.



  Publications

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

Labalette, C., Nouet, Y., Sobczak-Thepot, J., Armengol, C., Levillayer, F., Gendron, M. C., Renard, C. A., Regnault, B., Chen, J., Buendia, M. A., and Wei, Y. (2008). The LIM-only Protein FHL2 Regulates Cyclin D1 Expression and Cell Proliferation. J Biol Chem, 283: 15201-15208. PMID: 18378678

Labalette, C., Nouet, Y., Levillayer, F., Armengol, C., Renard, C. A., Soubigou, G., Xia, T., Buendia, M. A., and Wei, Y. (2008). The LIM-Only Protein FHL2 Mediates Ras-Induced Transformation through Cyclin D1 and p53 Pathways. PLoS ONE, 3: e3761. PMID: 19018287

Cairo, S., Armengol, C., De Reynies, A., Wei, Y., Thomas, E., Renard, C. A., Goga, A., Balakrishnan, A., Semeraro, M., Gresh, L., Pontoglio, M., Strick-Marchand, H., Levillayer, F., Nouet, Y., Rickman, D., Gauthier, F., Branchereau, S., Brugieres, L., Laithier, V., Bouvier, R., Boman, F., Basso, G., Michiels, J. F., Hofman, P., Arbez-Gindre, F., Jouan, H., Rousselet-Chapeau, M. C., Berrebi, D., Marcellin, L., Plenat, F., Zachar, D., Joubert, M., Selves, J., Pasquier, D., Bioulac-Sage, P., Grotzer, M., Childs, M., Fabre, M., and Buendia, M. A. (2008). Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell, 14: 471-484. PMID: 19061838.





Activity Reports 2009 - Institut Pasteur
If you have problems with this Web page, please write to rescom@pasteur.fr