DNA重排导致白蛋白-纤溶酶原激活剂转基因小鼠发生肝癌。

DNA rearrangement causes hepatocarcinogenesis in albumin-plasminogen activator transgenic mice.

作者信息

Sandgren E P, Palmiter R D, Heckel J L, Brinster R L, Degen J L

机构信息

Laboratory of Reproductive Physiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104.

出版信息

Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11523-7. doi: 10.1073/pnas.89.23.11523.

Hepatocyte-directed production of urokinase-type plasminogen activator (uPA) in transgenic mice is hepatotoxic. Infrequently, hepatocytes arise that do not express uPA, due to physical loss of transgene DNA, and these cells clonally repopulate the entire liver within 3 months of birth. Surprisingly, hepatic tumors appear in these mice beginning at 8 months of age despite the fact that uPA is not oncogenic or genotoxic. Analysis of the transgene locus reveals that tumors arise only from a particular subclass of transgene-deficient cells in which the entire transgene array, and possibly a significant amount of flanking DNA, is deleted. Considering that all transgene-deficient regenerative nodules undergo extensive replication but only a subset gives rise to tumors, we propose that loss of genomic DNA, not mitogenesis per se, is a primary carcinogenic determinant in this model of hepatocarcinogenesis.

在转基因小鼠中，肝细胞定向产生尿激酶型纤溶酶原激活剂（uPA）具有肝毒性。由于转基因DNA的物理丢失，偶尔会出现不表达uPA的肝细胞，这些细胞在出生后3个月内通过克隆方式重新占据整个肝脏。令人惊讶的是，尽管uPA既不是致癌基因也不是基因毒性物质，但这些小鼠在8个月大时开始出现肝肿瘤。对转基因位点的分析表明，肿瘤仅起源于转基因缺陷细胞的一个特定亚类，其中整个转基因阵列以及可能大量的侧翼DNA被删除。鉴于所有转基因缺陷的再生结节都经历广泛的复制，但只有一部分会产生肿瘤，我们提出基因组DNA的丢失，而非有丝分裂本身，是这种肝癌发生模型中的主要致癌决定因素。