Hansen L J, Tennant B C, Seeger C, Ganem D
Howard Hughes Medical Institute, San Francisco, California.
Mol Cell Biol. 1993 Jan;13(1):659-67. doi: 10.1128/mcb.13.1.659-667.1993.
Woodchucks infected with woodchuck hepatitis virus (WHV) and ground squirrels infected with ground squirrel hepatitis virus (GSHV) both develop hepatocellular carcinoma (HCC), but WHV-associated tumors arise more frequently and much earlier in life. These differences are preserved when the oncogenic potentials of the two viruses are examined in the same host (woodchucks). We examined RNA and genomic DNA from tumors arising from WHV- and GSHV-infected woodchucks to determine whether these viruses use the same oncogenic pathway. N-myc RNA was not expressed in normal liver but was expressed in 10 of 13 WHV-associated HCCs examined. Southern blot analysis showed that 7 of 17 WHV-induced tumors (41%) contained rearrangements at N-myc loci due to viral genomic integration. Six of these seven inserts affected N-myc2, and most of these were at the 5' end of the gene. In contrast, only two of seven GSHV-induced woodchuck HCCs expressed N-myc RNA, and only 1 of the 16 tumors (6%) contained a rearranged N-myc allele. The GSHV-associated HCCs all contained numerous viral insertions, so the low frequency of integration into N-myc loci by GSHV was not due to a general block to integration. Four of sixteen GSHV-induced tumors harbored amplified c-myc alleles, and five of seven GSHV tumors tested contained elevated c-myc RNA levels. By contrast, enhanced c-myc RNA levels were observed in only 2 of 13 WHV-induced HCC. We conclude that N-myc overexpression is a regular feature of WHV- but not GSHV-associated hepatocarcinogenesis in a common host. In contrast, c-myc transcriptional deregulation is rarely encountered in WHV-induced HCC but is frequent in GSHV-induced HCC.
感染土拨鼠肝炎病毒（WHV）的土拨鼠和感染地松鼠肝炎病毒（GSHV）的地松鼠都会发生肝细胞癌（HCC），但与WHV相关的肿瘤发生频率更高，且在生命早期出现得更早。当在同一宿主（土拨鼠）中检测这两种病毒的致癌潜力时，这些差异仍然存在。我们检测了来自感染WHV和GSHV的土拨鼠所产生肿瘤的RNA和基因组DNA，以确定这些病毒是否使用相同的致癌途径。N-myc RNA在正常肝脏中不表达，但在所检测的13例与WHV相关的HCC中有10例表达。Southern印迹分析表明，17例由WHV诱导的肿瘤中有7例（41%）由于病毒基因组整合而在N-myc基因座处发生重排。这7个插入片段中有6个影响N-myc2，且大多数位于该基因的5'端。相比之下，7例由GSHV诱导的土拨鼠HCC中只有2例表达N-myc RNA，16例肿瘤中只有1例（6%）含有重排的N-myc等位基因。与GSHV相关的HCC都含有大量病毒插入片段，因此GSHV整合到N-myc基因座的频率较低并非由于普遍的整合障碍。16例由GSHV诱导的肿瘤中有4例含有扩增的c-myc等位基因，7例检测的GSHV肿瘤中有5例c-myc RNA水平升高。相比之下，13例由WHV诱导的HCC中只有2例观察到c-myc RNA水平升高。我们得出结论，在共同宿主中，N-myc过表达是与WHV相关而非与GSHV相关的肝癌发生的一个常见特征。相比之下，c-myc转录失调在WHV诱导的HCC中很少见，但在GSHV诱导的HCC中很常见。
