Lack of WHV integration nearby N-myc2 and in the downstream b3n and win loci in a considerable fraction of liver tumors with activated N-myc2 from naturally infected wild woodchucks
Lack of WHV integration nearby N-myc2 and in the downstream b3n and win loci in a considerable fraction of liver tumors with activated N-myc2 from naturally infected wild woodchucks
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DOI：
10.1016/j.virol.2005.09.061
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发表时间：
2006-02-05
期刊：
影响因子：
3.7
通讯作者：
Rapicetta, M
中科院分区：
文献类型：
--
作者：
Bruni, R;Conti, I;Rapicetta, M
在WHV/土拨鼠HBV感染模型中，慢性WHV感染诱导的肝肿瘤中，WHV插入激活myc家族基因已被充分证实。一些研究表明，N-myc 2是迄今为止最常见的参与，在大多数情况下，其转录激活是由于WHV插入附近的基因。N-myc 2也被WHV插入两个下游位点b3 n和win激活。尽管在土拨鼠肿瘤中这些后一个位点中的插入程度尚未被研究，但他们的发现导致了这样的概念，即其中WHV插入解释了在表达原癌基因的剩余肿瘤中在基因附近没有任何可检测的改变的情况下N-myc 2的激活，这一概念仍然未经证实，并且尚未进一步研究。上述观察结果来自于实验室繁殖的土拨鼠，土拨鼠用标准化的病毒接种物进行实验性感染，大多数是同一谱系的土拨鼠。在目前的工作中，我们调查了在自然获得的慢性WHV感染的野生土拨鼠中自然发生的肝脏肿瘤的调查。肿瘤具有高至中等分化的HCC的组织学特征。在大多数动物中，观察到多个肿瘤结节;在绝大多数情况下，它们被证明是独立的肿瘤，因为它们的WHV整合模式与克隆无关。我们对53个独立的肿瘤进行了N-myc激活和WHV整合的研究，发现在自然感染的野生土拨鼠肿瘤中，WHV整合在N-myc基因附近的频率有降低的趋势，另外，N-myc 2激活是由于WHV整合在基因附近，其频率显著低于实验感染的集落出生动物的肿瘤（12/28，43% vs. 15/20，75%，P = 0.0397）。这些发现可能与自然感染的野生土拨鼠中的感染病毒和宿主遗传背景相对于实验感染的群体出生的土拨鼠的不太一致的条件有关，并且表明病毒和/或宿主因素可能影响最终在明显肿瘤中检测到的病毒插入位点。（11/28，39%）N-myc 2转录激活的肿瘤在基因附近、b3 n或win中均未显示重排。这些发现挑战了下游b3 n和win基因座的整合是N-myc 2激活的原因，在N-myc 2附近缺乏插入的肿瘤中，并表明在相当一部分肝肿瘤中，至少从野生土拨鼠，N-myc 2激活可能是由于WHV整合在N-myc 2染色体结构域的其他区域或其他与病毒插入相关或不相关的机制。(C)2005年爱思唯尔公司All rights reserved.
In liver tumors induced by chronic WHV infection in the WHV/woodchuck model of HBV infection, activation of genes of the myc family by WHV insertion has been well documented. Several studies have shown that N-myc2 is by far the most frequently involved, and in most cases, its transcriptional activation is due to WHV insertion nearby the gene. N-myc2 has been shown to be also activated by WHV insertion in two downstream loci, b3n and win. Although the extent of insertion in these latter loci in woodchuck tumors has not been investigated, their discovery has led to the notion that therein WHV insertion accounts for N-myc2 activation in the remaining tumors expressing the proto-oncogene in absence of any detectable alteration nearby the gene, a notion remained unproved and not further investigated yet.In the majority of cases, the above observations were derived from tumors developed in colony born laboratory bred woodchucks experimentally infected with standardized viral inocula, mostly of the same lineage.In the present work, we investigated a survey of liver tumors naturally developed in wild woodchucks with naturally acquired chronic WHV infection. Tumors had histological features of well to moderately differentiated HCCs. In most animals, multiple tumor nodules were observed; in the great majority of cases, they were shown to be independent tumors because their WHV integration patterns were not clonally related. 53 independent tumors were investigated for N-myc activation and WHV integration nearby N-myc genes and in the b3n and win loci.Comparison of our results with data from previous studies revealed that, in tumors from naturally infected wild woodchucks, the frequency of WHV integration nearby N-myc2 has a tendency to be lower and, in addition, N-myc2 activation is due to WHV integration nearby the gene significantly less frequently than in tumors from experimentally infected colony born animals (12/28, 43% vs. 15/20, 75%, P = 0.0397). These findings are likely related to the less uniform conditions as to infecting virus and host genetic background in naturally infected wild woodchucks with respect to experimentally infected colony born woodchucks and suggest that viral and/or host factors may influence the site of viral insertion finally detected in overt tumors.In addition, more than one third (11/28, 39%) tumors with activated N-myc2 transcription did not show rearrangement either nearby the gene, or in b3n or in win. These findings challenge the notion that integration in the downstream b3n and win loci is responsible for N-myc2 activation in tumors lacking insertion nearby N-myc2 and suggest that in a considerable fraction of liver tumors, at least from wild woodchucks, N-myc2 activation might be due either to WHV integration in further regions of the N-myc2 chromosomal domain or to other mechanisms related or unrelated to viral insertion. (C) 2005 Elsevier Inc. All rights reserved.