Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey.
Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey.
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DOI：
10.1038/onc.2014.223
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发表时间：
2015-05-21
期刊：
影响因子：
8
通讯作者：
Leach SD
中科院分区：
文献类型：
--
作者：
Park JT;Johnson N;Liu S;Levesque M;Wang YJ;Ho H;Huso D;Maitra A;Parsons MJ;Prescott JD;Leach SD
KRAS原癌基因的体细胞激活在几乎所有胰腺癌中都是明显的，并且似乎代表了起始事件。这些突变主要发生在密码子12，较少发生在密码子13和61。虽然一些研究表明，不同的KRAS突变可能具有可变的致癌特性，但迄今为止，在体内脊椎动物肿瘤发生系统中，尚未对多种KRAS突变进行全面的功能比较。我们建立了一个基于Gal 4/UAS的斑马鱼胰腺肿瘤发生模型，其中UAS调节的癌基因的胰腺表达由ptf 1a：Gal 4-VP 16驱动线驱动。该系统允许我们快速比较12种不同KRAS突变（G12 A、G12 C、G12 D、G12 F、G12 R、G12 S、G12 V、G13 C、G13 D、Q61 L、Q61 R和A146 T）在体内驱动胰腺肿瘤发生的能力。在注射了在其他肿瘤类型中报告的五种KRAS突变之一但在人胰腺癌中未报告的鱼中，2/79（0.25%）发生胰腺肿瘤，两种肿瘤都发生在注射了A146 T的鱼中。相比之下，在注射了已知在人类胰腺癌中发生的七种KRAS突变之一的鱼类中，22/106（20.8%）发生了胰腺癌。所有8种致瘤性KRAS突变均与癌前胰腺上皮中下游MAPK/ERK通路激活相关，而非致瘤性突变则不相关。这些结果表明，在人胰腺癌中观察到的KRAS突变谱反映了基于可变致瘤能力的选择，包括激活MAPK/ERK信号传导的能力。
Somatic activation of the KRAS proto-oncogene is evident in almost all pancreatic cancers, and appears to represent an initiating event. These mutations occur primarily at codon 12 and less frequently at codons 13 and 61. While some studies have suggested that different KRAS mutations may have variable oncogenic properties, to date there has been no comprehensive functional comparison of multiple KRAS mutations in an in vivo vertebrate tumorigenesis system. We generated a Gal4/UAS-based zebrafish model of pancreatic tumorigenesis in which the pancreatic expression of UAS-regulated oncogenes is driven by a ptf1a:Gal4-VP16 driver line. This system allowed us to rapidly compare the ability of 12 different KRAS mutations (G12A, G12C, G12D, G12F, G12R, G12S, G12V, G13C, G13D, Q61L, Q61R, and A146T) to drive pancreatic tumorigenesis in vivo. Among fish injected with one of five KRAS mutations reported in other tumor types but not in human pancreatic cancer, 2/79 (0.25%) developed pancreatic tumors, with both tumors arising in fish injected with A146T. In contrast, among fish injected with one of seven KRAS mutations known to occur in human pancreatic cancer, 22/106 (20.8%) developed pancreatic cancer. All eight tumorigenic KRAS mutations were associated with downstream MAPK/ERK pathway activation in preneoplastic pancreatic epithelium, while non-tumorigenic mutations were not. These results suggest that the spectrum of KRAS mutations observed in human pancreatic cancer reflects selection based upon variable tumorigenic capacities, including the ability to activate MAPK/ERK signaling.