FREQUENT ACTIVATION OF N-MYC GENES BY HEPADNAVIRUS INSERTION IN WOODCHUCK LIVER-TUMORS
FREQUENT ACTIVATION OF N-MYC GENES BY HEPADNAVIRUS INSERTION IN WOODCHUCK LIVER-TUMORS
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DOI：
10.1038/347294a0
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发表时间：
1990-09-20
期刊：
影响因子：
64.8
通讯作者：
BUENDIA, MA
中科院分区：
文献类型：
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作者：
FOUREL, G;TREPO, C;BUENDIA, MA
最近通过在两个独立的肝细胞癌中插入土拨鼠肝炎病毒 DNA 来激活 ofc-myc-myc 的发现支持了这样的假设：在大多数人类和土拨鼠肝脏肿瘤中观察到的乙型肝炎病毒整合到宿主基因组中 2,3 可能有助于肿瘤发生。我们在此报告了土拨鼠肝炎病毒 DNA 在两个新鉴定的 N-myc 基因中的高频率整合：N-myc1（已知哺乳动物 N-myc 基因的同源物）和 N-myc2（一种无内含子“互补 DNA 基因”或“逆转录子”，与 N-myc 保留了广泛的编码和转化同源性。 N-myc2 在正常肝脏中完全沉默，但在大多数肝脏肿瘤中过度表达，没有基因重排。此外，大约20%的肿瘤中，病毒整合发生在N-myc1或N-myc2内，产生嵌合信使RNA，其中N-myc的3'非翻译区被包含病毒增强子的土拨鼠肝炎病毒序列取代。插入位点聚集在第三个外显子的短序列中，该序列与小鼠 N-myc 基因内的逆转录病毒整合热点一致，最近在小鼠白血病病毒诱导的 T 细胞淋巴瘤中进行了描述4-6。因此，导致N-mycgenes表达失调的类似机制可能在啮齿类动物中由肝炎病毒或非急性逆转录病毒诱导的肿瘤的发展中起作用。现在，通过插入嗜肝DNA病毒DNA来激活myc基因已成为土拨鼠肝细胞癌发生过程中的常见事件。
THE recent finding ofc-mycactivation by insertion of woodchuck hepatitis virus DNA in two independent hepatocellular carcinoma1has given support to the hypothesis that integration of hepatitis B viruses into the host genome, observed in most human and woodchuck liver tumours2,3, might contribute to oncogenesis. We report here high frequency of woodchuck hepatitis virus DNA integrations in two newly identified N-mycgenes: N-myc1, the homologue of known mammalian N-mycgenes, and N-myc2, an intronless 'complementary DNA gene' or 'retroposon' that has retained extensive coding and transforming homology with N-myc. N-myc2is totally silent in normal liver, but is overexpressed without genetic rearrangements in most liver tumours. Moreover, viral integrations occur within either N-myc1or N-myc2in about 20% of the tumours, giving rise to chimaeric messenger RNAs in which the 3' untranslated region of N-mycwas replaced by wood-chuck hepatitis virus sequences encompassing the viral enhancer. Insertion sites were clustered in a short sequence of the third exon that coincides with a retroviral integration hotspot within the murine N-mycgene, recently described in T-cell lymphomas induced by murine leukaemia virus4–6. Thus, comparable mechan-isms, leading to deregulated expression of N-mycgenes, may operate in the development of tumours induced either by hepatitis virus or by nonacute retroviruses in rodents. Activation ofmycgenes by insertion of hepadnavirus DNA now emerges as a common event in the genesis of woodchuck hepatocellular carcinoma.