Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis
Mutationally activated K-ras 4A and 4B both mediate lung carcinogenesis
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DOI：
10.1016/j.yexcr.2007.11.004
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发表时间：
2008-03-10
影响因子：
3.7
通讯作者：
Hooper, Martin L.
中科院分区：
文献类型：
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作者：
Patek, Charles E.;Arends, Mark J.;Hooper, Martin L.
为了研究内源性K-ras 4A和K-ras 4 B剪接变异体在肿瘤发生中的作用，用N-甲基-N-亚硝基脲（MNU）诱导小鼠肺癌发生，MNU导致K-ras突变（G12 D），共同影响两种亚型。与年龄匹配的K-ras（tmA 4A/-）小鼠（肿瘤仅表达突变激活的K-ras 4 B）相比，K-ras（+/-）小鼠（肿瘤也表达突变激活的K-ras 4A）的肿瘤数量和大小显著更高，K-TaStm Delta 4A/tm Delta 4A小鼠（肿瘤同时表达野生型和激活的K-ras 4 B）的肿瘤数量和大小显著更低。MNU在野生型小鼠中诱导的肿瘤明显多于K-ras（tm Delta 4A/tm Delta 4A）小鼠，其不同之处在于只有野生型小鼠中的肿瘤可以表达野生型和活化的K-ras 4A。所有基因型的肺肿瘤主要是乳头状腺瘤，K-ras（+/-）和K-ras（tm Delta 4A/-）小鼠的肿瘤显示磷酸化Erk 1/2和磷酸化Akt染色。因此，（1）突变激活的K-ras 4 B足以激活Raf/MEK/ERK（MAPK）和P13-K/Akt途径，并启动肺肿瘤发生，（2）当与激活的K-ras 4 B一起表达时，突变激活的K-ras 4A进一步促进肺肿瘤的形成和生长（在存在和不存在其野生型同种型的情况下），但不影响肿瘤病理或进展，和（3）野生型K-ras 4 B，直接或间接，减少肿瘤数量和大小。(c)2007年爱思唯尔公司All rights reserved.
To examine the roles of endogenous K-ras 4A and K-ras 4B splice variants in tumorigenesis, murine lung carcinogenesis was induced by N-methyl-N-nitrosourea (MNU), which causes a K-ras mutation (G12D) that jointly affects both isoforms. Compared with age-matched K-raS(tmA4A/-) mice (where tumours can express mutationally activated K-ras 4B only), tumour number and size were significantly higher in K-ras(+/-) mice (where tumours can also express mutationally activated K-ras 4A), and significantly lower in K-TaStm Delta 4A/tm Delta 4A mice (where tumours can express both wild-type and activated K-ras 4B). MNU induced significantly more, and larger, tumours in wild-type than K-ras(tm Delta 4A/tm Delta 4A) mice which differ in that only tumours in wild-type mice can express wild-type and activated K-ras 4A. Lung tumours in all genotypes were predominantly papillary adenomas, and tumours from K-ras(+/-) and K-ras(tm Delta 4A/-) mice exhibited phospho-Erk1/2 and phospho-Akt staining. Hence (1) mutationally activated K-ras 4B is sufficient to activate the Raf/MEK/ERK(MAPK) and P13-K/Akt pathways, and initiate lung tumorigenesis, (2) when expressed with activated K-ras 4B, mutationally activated K-ras 4A further promotes lung tumour formation and growth (both in the presence and absence of its wild-type isoform) but does not affect either tumour pathology or progression, and (3) wild-type K-ras 4B, either directly or indirectly, reduces tumour number and size. (c) 2007 Elsevier Inc. All rights reserved.