Hepatitis B virus X protein promotes the growth of hepatocellular carcinoma by modulation of the Notch signaling pathway

Hepatitis B virus X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma (HCC), however, little is known about the mechanism. Here, we investigated the relationship between HBx and Notch signaling in HepG2 cells after they were transfected with the HBx gene. It was found that HBx upregulated the expression of Notch-1, Jagged-1 and Hes-1 at the transcriptional level by binding to the Notch-1 intracellular domain, which is congruent with the observations of enhanced malignant biological activities of HBx-transfected HepG2 cells compared with normal HepG2 cells. However, while Notch signaling was blocked, the HBx-induced abnormalities were partially reversed. These findings suggest that HBx may promote the progression of HCC via the activated Notch pathway.

[1]  Hugo J. Bellen,et al.  Notch Signaling , 2014, Methods in Molecular Biology.

[2]  A. Graessmann,et al.  The hepatitis B virus HBx protein inhibits caspase 3 activity. , 2013, The Journal of Biological Chemistry.

[3]  Chunyan Liu,et al.  The effects of HBx gene on the expression of DNA repair enzymes hOGG1 and hMYHα mRNA in HepG2 cells , 2009, Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban.

[4]  D. Fan,et al.  Expression of Jagged1 and its association with hepatitis B virus X protein in hepatocellular carcinoma. , 2007, Biochemical and biophysical research communications.

[5]  C. Manetopoulos,et al.  The Notch pathway in cancer: differentiation gone awry. , 2005, European journal of cancer.

[6]  M. Herlyn,et al.  Activation of Notch1 signaling is required for beta-catenin-mediated human primary melanoma progression. , 2005, The Journal of clinical investigation.

[7]  Jun Qin,et al.  Erk Associates with and Primes GSK-3β for Its Inactivation Resulting in Upregulation of β-Catenin , 2005 .

[8]  Jun Qin,et al.  Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. , 2005, Molecular cell.

[9]  H. El‐Serag,et al.  Hepatocellular carcinoma: recent trends in the United States. , 2004, Gastroenterology.

[10]  Alan D. Lopez,et al.  Global and regional estimates of cancer mortality and incidence by site: II. results for the global burden of disease 2000 , 2002, BMC Cancer.

[11]  J. Aster,et al.  Notch Signaling in Cancer , 2002, Cancer biology & therapy.

[12]  S. Hubscher,et al.  Altered Notch ligand expression in human liver disease: further evidence for a role of the Notch signaling pathway in hepatic neovascularization and biliary ductular defects. , 2002, The American journal of pathology.

[13]  S. Hubscher,et al.  Notch receptor expression in adult human liver: A possible role in bile duct formation and hepatic neovascularization , 2001, Hepatology.

[14]  T. Ohtsuka,et al.  Roles of the Basic Helix-Loop-Helix Genes Hes1 and Hes5 in Expansion of Neural Stem Cells of the Developing Brain* , 2001, The Journal of Biological Chemistry.

[15]  S. Do,et al.  The Hepatitis B Virus-X Protein Activates a Phosphatidylinositol 3-Kinase-dependent Survival Signaling Cascade* , 2001, The Journal of Biological Chemistry.

[16]  T. Honjo,et al.  Identification of Notch1 as a Frequent Target for Provirus Insertional Mutagenesis in T-Cell Lymphomas Induced by Leukemogenic Mutants of Mouse Mammary Tumor Virus , 2000, Journal of Virology.

[17]  B. Osborne,et al.  Notch and the immune system. , 1999, Immunity.

[18]  S. Artavanis-Tsakonas,et al.  Notch Signaling : Cell Fate Control and Signal Integration in Development , 1999 .

[19]  R. Schneider,et al.  Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras , 1997, Molecular and cellular biology.

[20]  R. Schneider,et al.  Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Lucito,et al.  The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. , 1995, The EMBO journal.

[22]  Christel Brou,et al.  Signalling downstream of activated mammalian Notch , 1995, Nature.

[23]  K. Koike.  Hepatitis B virus HBx gene and hepatocarcinogenesis. , 1995, Intervirology.

[24]  R. Schneider,et al.  Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  P. Hofschneider,et al.  Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway , 1993, Nature.

[26]  R. Lucito,et al.  Hepatitis B virus X protein activates transcription factor NF-kappa B without a requirement for protein kinase C , 1992, Journal of virology.

[27]  J. Sklar,et al.  TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms , 1991, Cell.

[28]  A. Siddiqui,et al.  HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions , 1991, Science.

[29]  D. Woodfield.  Hepatocellular carcinoma. , 1986, The New Zealand medical journal.