Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Carcinogenesis. 2011 Aug;32(8):1279-84. doi: 10.1093/carcin/bgr097. Epub 2011 May 30.
Lung tumors from smokers as well as lung tumors from mice exposed to tobacco carcinogens such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), often carry mutations in K-ras, which activates downstream-signaling pathways such as PI3K/AKT/mTOR pathway. Mice with genetic deletion of one of three isoforms of AKT were used to investigate the role of AKT in mutant K-ras-induced lung tumorigenesis in mice. Although deletion of Akt1 or Akt2 decreased NNK-induced lung tumor formation by 90%, deletion of Akt2 failed to decrease lung tumorigenesis in two other mouse models driven by mutant K-ras. Genetic mapping showed that Akt2 was tightly linked to the cytochrome P450 Cyp2a locus on chromosome 7. Consequently, targeted deletion of Akt2 created linkage to a strain-specific Cyp2a5 polymorphism that decreased activation of NNK in vitro. Mice with this Cyp2a5 polymorphism had decreased NNK-induced DNA adduct formation in vivo and decreased NNK-induced lung tumorigenesis. These studies support human epidemiological studies linking CYP2A polymorphisms with lung cancer risk in humans and highlight the need to confirm phenotypes of genetically engineered mice in multiple mouse strains.
吸烟者的肺部肿瘤以及暴露于烟草致癌物质（如 4-（甲基亚硝氨基）-1-（3-吡啶基）-1-丁酮（NNK））的小鼠的肺部肿瘤，通常携带 K-ras 突变，该突变激活下游信号通路，如 PI3K/AKT/mTOR 通路。使用基因敲除 Akt1 或 Akt2 的三种同工型之一的小鼠来研究 Akt 在突变型 K-ras 诱导的小鼠肺部肿瘤发生中的作用。尽管 Akt1 或 Akt2 的缺失将 NNK 诱导的肺肿瘤形成减少了 90%，但 Akt2 的缺失未能减少另外两种由突变型 K-ras 驱动的小鼠模型中的肺肿瘤发生。遗传图谱显示 Akt2 与 7 号染色体上的细胞色素 P450 Cyp2a 基因座紧密连锁。因此，Akt2 的靶向缺失导致与一种特定于品系的 Cyp2a5 多态性相关联，该多态性降低了 NNK 的体外激活。具有这种 Cyp2a5 多态性的小鼠体内的 NNK 诱导的 DNA 加合物形成减少，并且 NNK 诱导的肺肿瘤发生减少。这些研究支持将 CYP2A 多态性与人类肺癌风险相关的人类流行病学研究，并强调需要在多个小鼠品系中确认基因工程小鼠的表型。
