Wildtype Kras2 can inhibit lung carcinogenesis in mice
Wildtype Kras2 can inhibit lung carcinogenesis in mice
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DOI：
10.1038/ng721
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发表时间：
2001-09-01
期刊：
影响因子：
30.8
通讯作者：
You, M
中科院分区：
文献类型：
--
作者：
Zhang, ZQ;Wang, Y;You, M
虽然ras基因早已被确定为原癌基因，但激活的ras在细胞转化中的主导作用一直受到质疑。先前的研究表明，野生型Kras 2等位基因在小鼠和人肺腺癌中频繁丢失。为了解决野生型Kras 2在肺肿瘤发生中可能的肿瘤抑制作用，我们在杂合Kras 2缺陷小鼠中进行了肺肿瘤生物测定。与野生型小鼠相比，具有杂合Kras 2缺陷的小鼠对肺肿瘤的化学诱导高度敏感。在所有化学诱导的肺肿瘤中检测到激活Kras 2突变，这些肿瘤来自野生型和杂合Kras 2缺陷小鼠。此外，野生型Kras 2抑制转化的NIH/3 T3细胞和含有激活的Kras 2等位基因的小鼠肺肿瘤细胞系的集落形成和肿瘤发展。野生型Kras 2的等位基因丢失在67%至100%的化学诱导的小鼠肺腺癌中发现，这些小鼠肺腺癌含有突变型Kras 2等位基因。最后，在这些细胞中观察到野生型Kras 2表达水平与细胞外信号调节激酶（ERK）活性之间的负相关性。这些数据有力地表明，野生型Kras 2具有肿瘤抑制活性，并且在肺肿瘤进展过程中经常丢失。
Although the ras genes have long been established as proto-oncogenes, the dominant role of activated ras in cell transformation has been questioned. Previous studies have shown frequent loss of the wildtype Kras2 allele in both mouse and human lung adenocarcinomas. To address the possible tumor suppressor role of wildtype Kras2 in lung tumorigenesis, we have carried out a lung tumor bioassay in heterozygous Kras2-deficient mice. Mice with a heterozygous Kras2 deficiency were highly susceptible to the chemical induction of lung tumors when compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells and a mouse lung tumor cell line containing an activated Kras2 allele. Allelic loss of wildtype Kras2 was found in 67% to 100% of chemically induced mouse lung adenocarcinomas that harbor a mutant Kras2 allele. Finally, an inverse correlation between the level of wildtype Kras2 expression and extracellular signal-regulated kinase (ERK) activity was observed in these cells. These data strongly suggest that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression.