Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene.
Integration of Hepatitis B Virus (HBV) DNA into liver cell DNA has been well established, but its implication in liver carcinogenesis is still being debated. In particular, insertion of the viral genome into cellular genes has been viewed as a rare event. By using HBV-Alu PCR, we have now isolated, from nine hepatocellular carcinomas, nine HBV-DNA integration sites showing that the viral genome mutates key regulatory cellular genes: neurotropic tyrosin receptor kinase 2 (NTRK2) gene, IL-1R-associated kinase 2 (IRAK2) gene, p42 mitogen-activated protein kinase 1 (p42MAPK1) gene, inositol 1,4,5-triphosphate receptor type 2 (IP3R2) gene, inositol 1,4,5-triphosphate receptor (IP3R) type 1 (IP3R1) gene, alpha 2,3 sialyltransferase (ST3GAL VI or SITA) gene, thyroid hormone uncoupling protein (TRUP) gene, EMX2-like gene, and human telomerase reverse transcriptase (hTERT) gene. This result brings to 15 the total number of genes targeted by HBV in a study of 22 human liver cancers. Overall, we found that both the inositol 1,4,5-triphosphate receptor gene and the telomerase gene were targeted by HBV in two different tumors. Thus, HBV frequently targets cellular genes involved in cell signalling and some of them may be preferential targets of the viral integration.
Paterlini-Bréchot
Patrizia
P
INSERM/Pasteur Unit 370, Necker Faculty of Medicine, Necker-Enfants Malades Hospital, Paris 75015, France. paterlini@necker.fr
Saigo
Kenichi
K
Murakami
Yoshiki
Y
Chami
Mounia
M
Gozuacik
Devrim
D
Mugnier
Claude
C
Lagorce
David
D
Bréchot
Christian
C
D015220:Calcium Channels / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000821:virology*; D004273:DNA, Neoplasm / Q000032:analysis*; D004279:DNA, Viral / Q000302:isolation & purification*; D004268:DNA-Binding Proteins / Q000235:genetics; D006509:Hepatitis B / Q000821:virology; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; D008113:Liver Neoplasms / Q000235:genetics / Q000821:virology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011494:Protein Kinases / Q000235:genetics; D020813:Receptor, trkB / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D012799:Sialyltransferases / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D016662:Virus Integration; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D015220:Calcium Channels; D004273:DNA, Neoplasm; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C506926:ITPR1 protein, human; C506927:ITPR2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009363:Neoplasm Proteins; C057838:RPL7A protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D012269:Ribosomal Proteins; C475774:THRAP3 protein, human; D014157:Transcription Factors; D012799:Sialyltransferases; D011494:Protein Kinases; D020813:Receptor, trkB; D053592:Interleukin-1 Receptor-Associated Kinases; D019950:Mitogen-Activated Protein Kinase 1; D019098:Telomerase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase