Integration of hepatiti's B virus DNA into the myeloid/lymphoid or mixed-lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma

被引:94
作者
Saigo, Kenichi
Yoshida, Kenichi [1 ]
Ikeda, Ryuji [1 ]
Sakamoto, Yoshiko [1 ]
Murakami, Yoshiki [2 ]
Urashima, Tetsuro
Asano, Takehide [3 ]
Kenmochi, Takashi
Inoue, Ituro [1 ,4 ]
机构
[1] Univ Tokyo, Inst Med Sci, Div Genet Diag, Tokyo, Japan
[2] Kyoto Univ, Grad Sch Med, Ctr Genom Med, Kyoto, Japan
[3] Teikyo Univ, Sch Med, Tokyo 173, Japan
[4] Tokai Univ, Sch Med, Div Mol Life Sci, Kanagawa 2591100, Japan
关键词
hepatocellular carcinoma; DNA integration; hepatitis B virus; HBx; MLL4;
D O I
10.1002/humu.20701
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Integration of hepatitis B virus (HBV) DNA into host DNA is detected in about 90% of HBV-related hepatocellular carcinoma (HCC), but the preferential sites of the viral integration etiologically relevant to oncogenesis have been controversial. By using an adaptor-ligation/suppression-PCR, we identified four integrations into the myeloid/lymphoid or mixed-lineage leukemia 4 (MLL4) gene from 10 HCC patients with positive HBV surface antigen (HBsAg). Determination of the cellular-virus DNA junction demonstrated that various lengths of the virus were integrated within 300bp of intron 3 flanked by the Alu element of MLL4. Chimeric hepatitis B virus X gene (HBx)/MLL4 transcripts and the HBx fusion proteins were detected. DNA microarray revealed that HBx/MLL4 fusion proteins suppressed unique genes in HepG2 cells. Finally, chromosomal translocations of intron 3 of MLL4 to the specific region of chromosome 17p11.2 in 22 out of 32 HCC patients were observed, showing that the intron 3 region of MLL4 gene would be a target of translocation breakpoint. In conclusion, the present data suggest that the translocation breakpoint of MLL4 gene is one of the preferential targets for HBV DNA integration into the MLL4 gene and the HBV DNA integration may be involved in liver oncogenesis.
引用
收藏
页码:703 / 708
页数:6
相关论文
共 17 条
[1]   Genomic DNA double-strand breaks are targets for hepadnaviral DNA integration [J].
Bill, CA ;
Summers, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (30) :11135-11140
[2]   Molecular viral oncology of hepatocellular carcinoma [J].
Block, TM ;
Mehta, AS ;
Fimmel, CJ ;
Jordan, R .
ONCOGENE, 2003, 22 (33) :5093-5107
[3]   Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) [J].
Bréchot, C ;
Gozuacik, D ;
Murakami, Y ;
Paterlini-Bréchot, P .
SEMINARS IN CANCER BIOLOGY, 2000, 10 (03) :211-231
[4]   Hepatitis B virus-related insertional mutagenesis implicates SERCA1 gene in the control of apoptosis [J].
Chami, M ;
Gozuacik, D ;
Saigo, K ;
Capiod, T ;
Falson, P ;
Lecoeur, H ;
Urashima, T ;
Beckmann, J ;
Gougeon, ML ;
Claret, M ;
le Maire, M ;
Bréchot, C ;
Paterlini-Bréchot, P .
ONCOGENE, 2000, 19 (25) :2877-2886
[5]   Amplification of DNA sequences from chromosome 19q13.1 in human pancreatic cell lines [J].
Curtis, LJ ;
Li, Y ;
Gerbault-Seureau, M ;
Kuick, R ;
Dutrillaux, AM ;
Goubin, G ;
Fawcett, J ;
Cram, S ;
Dutrillaux, B ;
Hanash, S ;
Muleris, M .
GENOMICS, 1998, 53 (01) :42-55
[6]   Increase in de novo HBV DNA integrations in response to oxidative DNA damage or inhibition of poly(ADP-ribosyl)ation [J].
Dandri, M ;
Burda, MR ;
Bürkle, A ;
Zuckerman, DM ;
Will, H ;
Rogler, CE ;
Greten, H ;
Petersen, J .
HEPATOLOGY, 2002, 35 (01) :217-223
[7]   Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers [J].
Ferber, MJ ;
Montoya, DP ;
Yu, C ;
Aderca, I ;
McGee, A ;
Thorland, EC ;
Nagorney, DM ;
Gostout, BS ;
Burgart, LJ ;
Boix, L ;
Bruix, J ;
McMahon, BJ ;
Cheung, TH ;
Chung, TKH ;
Wong, YF ;
Smith, DI ;
Roberts, LR .
ONCOGENE, 2003, 22 (24) :3813-3820
[8]   MLL2:: A new mammalian member of the trx/MLL family of genes [J].
FitzGerald, KT ;
Diaz, MO .
GENOMICS, 1999, 59 (02) :187-192
[9]   Identification of human cancer-related genes by naturally occurring Hepatitis B Virus DNA tagging [J].
Gozuacik, D ;
Murakami, Y ;
Saigo, K ;
Chami, M ;
Mugnier, C ;
Lagorce, D ;
Okanoue, T ;
Urashima, T ;
Bréchot, C ;
Paterlini-Bréchot, P .
ONCOGENE, 2001, 20 (43) :6233-6240
[10]   Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization [J].
Hsieh, JJD ;
Ernst, P ;
Erdjument-Bromage, H ;
Tempst, P ;
Korsmeyer, SJ .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (01) :186-194