Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17.
Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17.
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DOI：
10.1093/carcin/bgp054
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发表时间：
2009-05
期刊：
影响因子：
4.7
通讯作者：
Drinkwater NR
中科院分区：
文献类型：
--
作者：
Peychal SE;Bilger A;Pitot HC;Drinkwater NR
性激素影响近交系小鼠肝癌易感性。C57 BR/cdJ（BR）雌性对自发性和化学诱导的肝肿瘤非常敏感，部分原因是缺乏通常由卵巢激素提供的对肝癌发生的保护。BR雄性也是中度易感的，并且BR小鼠的两种性别对相对于抗性C57 BL/6 J（B6）品系的N，N-二乙基亚硝胺诱导的肝肿瘤的易感性是由分别位于染色体17和1上的两个被命名为Hcf 1和Hcf 2（雌性中的肝癌发生）的位点引起的。17号染色体上的Hcf 1基因座是BR小鼠肝癌的主要修饰因子。为了验证该基因座的存在并研究其与Hcf 2的潜在相互作用，产生了每个区域的同源小鼠。与B6对照组相比，B6.BR（D17 Mit 164-D17 Mit 2）区域的纯合性导致女性肝脏肿瘤多样性增加4倍，男性增加4.5倍。一系列的16个重组体覆盖整个同源区域的开发，以进一步缩小区域包含Hcf 1。与B6同胞相比，易感杂合重组体在女性中表现出3至7倍的效应，在男性中表现出1.5至2倍的效应。在易感品系的效果完全概括了杂合全长17号染色体同源的易感性，并进一步缩小了Hcf 1基因座的位置，从30.05至35.83 Mb的染色体的一个区域。
Sex hormones influence the susceptibility of inbred mice to liver cancer. C57BR/cdJ (BR) females are extremely susceptible to spontaneous and chemically induced liver tumors, in part due to a lack of protection against hepatocarcinogenesis normally offered by ovarian hormones. BR males are also moderately susceptible, and the susceptibility of both sexes of BR mice to liver tumors induced with N,N-diethylnitrosamine relative to the resistant C57BL/6J (B6) strain is caused by two loci designated Hcf1 and Hcf2 (hepatocarcinogenesis in females) located on chromosomes 17 and 1, respectively. The Hcf1 locus on chromosome 17 is the predominant modifier of liver cancer in BR mice. To validate the existence of this locus and investigate its potential interaction with Hcf2, congenic mice for each region were generated. Homozygosity for the B6.BR(D17Mit164-D17Mit2) region resulted in a 4-fold increase in liver tumor multiplicity in females and a 4.5-fold increase in males compared with B6 controls. A series of 16 recombinants covering the entire congenic region was developed to further narrow the area containing Hcf1. Susceptible heterozygous recombinants demonstrated a 3- to 7-fold effect in females and a 1.5- to 2-fold effect in males compared with B6 siblings. The effect in susceptible lines completely recapitulated the susceptibility of heterozygous full-length chromosome 17 congenics and furthermore narrowed the location of the Hcf1 locus to a single region of the chromosome from 30.05 to 35.83 Mb.
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