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
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
复制标题
DOI：
10.1002/humu.20701
复制
发表时间：
2008-05-01
期刊：
影响因子：
3.9
通讯作者：
Inoue, Ituro
中科院分区：
文献类型：
--
作者：
Saigo, Kenichi;Yoshida, Kenichi;Inoue, Ituro
约90%的B肝炎病毒（HBV）相关肝细胞癌（HCC）中可检测到HBV DNA整合入宿主DNA，但HBV DNA整合的优先位点在病因学上与肿瘤发生相关一直存在争议。通过使用衔接子连接/抑制PCR，我们确定了四个整合到骨髓/淋巴或混合谱系白血病4（MLL 4）基因从10例肝癌患者与阳性HBV表面抗原（HBsAg）。细胞-病毒DNA连接的测定表明，不同长度的病毒整合在MLL 4的Alu元件侧翼的内含子3的300 bp内。检测嵌合B病毒X基因（HBx）/MLL 4转录本及HBx融合蛋白。DNA微阵列显示HBx/MLL 4融合蛋白抑制HepG 2细胞中的独特基因。在32例HCC患者中，有22例发生MLL 4内含子3易位到染色体17p11.2的特异区域，提示MLL 4内含子3区域可能是易位断裂点的靶点。结论：MLL 4基因的易位断裂点是HBV DNA整合入MLL 4基因的优先靶点之一，HBV DNA整合可能参与了肝癌的发生。
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.