Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo.
Oncogenic Kras requires simultaneous PI3K signaling to induce ERK activation and transform thyroid epithelial cells in vivo.
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DOI：
10.1158/0008-5472.can-09-0024
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Di Cristofano A
中科院分区：
文献类型：
--
作者：
Miller KA;Yeager N;Baker K;Liao XH;Refetoff S;Di Cristofano A
由滤泡细胞引起的甲状腺肿瘤经常发生突变，导致PI3K和Ras信号级联的组成性激活。然而，目前尚不清楚它们各自对肿瘤过程的贡献，以及它们在多大程度上相互作用。我们使用携带Kras致癌突变和靶向甲状腺上皮的Pten缺失的小鼠来解决体内这些问题。在这里，我们表明，虽然这两种途径中的每一种单独都不能转化甲状腺滤泡细胞，但它们的同时激活是高度致癌的，导致浸润性和转移性滤泡癌。特别是，PI3K的激活抑制了kras发起的反馈信号，使MEK和ERK激活分离，从而抑制了MAPK的活性；此外，PI3K和Kras共同上调cyclin D1 mRNA水平。最后，PI3K和MAPK的联合药理抑制完全抑制了双突变癌细胞系的生长，为甲状腺癌中这些途径的双重靶向提供了令人信服的理论依据。
Thyroid tumors arising from the follicular cells often harbor mutations leading to the constitutive activation of the PI3K and Ras signaling cascades. However, it is still unclear what their respective contribution to the neoplastic process is, as well as to what extent they interact. We have used mice harboring a Kras oncogenic mutation and a Pten deletion targeted to the thyroid epithelium to address in vivo these questions. Here we show that while each of these two pathways, alone, is unable to transform thyroid follicular cells, their simultaneous activation is highly oncogenic, leading to invasive and metastatic follicular carcinomas. In particular, PI3K activation suppressed Kras-initiated feedback signals that uncouple MEK and ERK activation, thus stunting MAPK activity; in addition, PI3K and Kras cooperated to drastically up-regulate cyclin D1 mRNA levels. Finally, combined pharmacological inhibition of PI3K and MAPK completely inhibited the growth of double mutant cancer cell lines, providing a compelling rationale for the dual targeting of these pathways in thyroid cancer.