Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon
Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon
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DOI：
10.1038/ng.115
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发表时间：
2008-05-01
期刊：
影响因子：
30.8
通讯作者：
Jacks, Tyler
中科院分区：
文献类型：
--
作者：
Haigis, Kevin M.;Kendall, Krystle R.;Jacks, Tyler
Kras在结肠癌中通常发生突变，但Nras的突变很罕见。我们利用基因工程小鼠来确定这些相关的癌基因是否以及如何调节结肠内的稳态和肿瘤发生。结肠上皮中K - Ras（G12D）的表达以一种依赖Mek的方式刺激细胞过度增殖。N - Ras（G12D）没有改变上皮的生长特性，但能够赋予细胞抗凋亡能力。在Apc突变的结肠肿瘤背景下，K - Ras的激活导致肿瘤上皮内终末分化缺陷以及假定干细胞的扩增。这种K - Ras肿瘤表型与通过MAPK途径的信号减弱有关，并且表达突变K - Ras的人类结肠癌细胞对Raf的抑制高度敏感，但对Mek的抑制不敏感。这些研究表明突变的Kras和Nras之间存在明显的表型差异，并提示突变K - Ras的致癌表型可能是由通过Ras效应途径的非经典信号传导所介导的。
Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.