Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas:: development of a novel mouse lung tumor model
Conditional expression of the mutant Ki-rasG12C allele results in formation of benign lung adenomas:: development of a novel mouse lung tumor model
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DOI：
10.1093/carcin/bgi190
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发表时间：
2005-12-01
期刊：
影响因子：
4.7
通讯作者：
Miller, MS
中科院分区：
文献类型：
--
作者：
Floyd, HS;Farnsworth, CL;Miller, MS
为了确定突变型Ki-ras基因的表达在肺肿瘤发生中的作用，我们建立了一种双基因小鼠模型，该模型以四环素诱导的肺特异性方式在肺泡II型和/或Clara细胞中表达人Ki-ras(G12C)等位基因。在12个月的时间里，Ki-ras(G12C)的表达导致了多个小的肺部肿瘤。尽管随着Ki-ras的持续表达，肿瘤的多样性增加，但大多数肺部病变是增生性或高分化腺瘤。这与在其他转基因小鼠模型中观察到的更严重的表型形成了鲜明对比，在这些模型中，不同突变的Ki-ras等位基因在肺中表达。Ki-ras(G12C)的表达与RAS和RAL信号通路的激活以及RAS下游效应因子，包括ERK、p90核糖体S6激酶、核糖体S6蛋白、p38和MAPKAPK-2的磷酸化增加有关。相反，转基因的表达对JNK和Akt信号通路的激活没有影响。停用多西环素1个月后，几乎完全没有肺增生性病变，提示肿瘤在没有Ki-ras表达的情况下消退。突变型Ki-ras(G12C)的表达足以维持肿瘤的表型，并通过激活多条效应通路诱导肺上皮细胞转化。这些结果描述了一种新的小鼠肺肿瘤模型，该模型显示了在没有肿瘤进展的情况下良性肿瘤的发展，这将为理解肺癌发病的早期阶段提供新的工具。
To determine the effects of expression of mutant Ki-ras on lung tumorigenesis, we developed a bitransgenic mouse model that expresses the human Ki-ras(G12C) allele in alveolar type II and/or Clara cells in a tetracycline-inducible, lung-specific manner. Expression of Ki-ras(G12C) caused multiple, small lung tumors over a 12-month time period. Although tumor multiplicity increased upon continued Ki-ras expression, most lung lesions were hyperplasias or well-differentiated adenomas. This is in contrast to the more severe phenotypes observed in other transgenic mouse models in which different mutant Ki-ras alleles were expressed in the lung. Expression of Ki-ras(G12C) was associated with a 2-fold increase in the activation of the Ras and Ral signaling pathways and increased phosphorylation of Ras downstream effectors, including Erk, p90 ribosomal S6 kinase, ribosomal S6 protein, p38 and MAPKAPK-2. In contrast, expression of the transgene had no effect on the activation of the JNK and Akt signaling pathways. Withdrawal of doxycycline for 1 month resulted in almost a complete absence of proliferative pulmonary lesions, suggesting tumor regression in the absence of Ki-ras expression. Mutant Ki-ras(G12C) expression was sufficient for initial lung tumor transformation, required for maintenance of tumor phenotype, and induced transformation of lung epithelial cells by the activation of multiple effector pathways. These results describe a novel mouse lung tumor model demonstrating benign tumor development in the absence of tumor progression, which will provide a new tool for understanding the early stages of lung tumor pathogenesis.