Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human Lung carcinomas
Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human Lung carcinomas
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DOI：
10.1016/j.humpath.2010.05.025
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发表时间：
2011-02-01
期刊：
影响因子：
3.3
通讯作者：
Ooi, Akishi
中科院分区：
文献类型：
--
作者：
Dobashi, Yoh;Suzuki, Shioto;Ooi, Akishi
分析了肺癌中表皮生长因子受体（EGFR）的表达/活化及其与下游调节蛋白Akt、哺乳动物雷帕霉素靶蛋白（mTOR）、p70 S6激酶（S6 K）、核糖体蛋白S6（rS6）和真核起始因子4 E结合蛋白1（4 E-BP 1）磷酸化状态的相关性，并评估了EGFR/Akt信号传导。免疫组化结果显示140例中EGFR过表达率为37.9%，磷酸化表达率为37.1%，而小细胞癌中EGFR过表达率较低。结合免疫印迹分析显示，当EGFR被激活时，60%的病例中至少有一个mTOR/S6 K或mTOR/4 E-BPI级联被激活。此外，在17.9%的非小细胞肺癌（NSCLC）中发现了EGFR-Akt-mTOR的组成性激活。对于每种蛋白质，激活的频率在组织学类型之间变化。在腺癌（AC）中，90%显示mTOR激活，无论EGFR状态如何，其中60%显示下游S6 K/rS6激活。此外，EGFR的突变经常伴随EGFR的磷酸化，并且在50%的携带EGFR突变的癌（包括鳞状细胞癌（SCC））中观察到通过rS6的整个EGFR的组成性激活。通过临床病理分析，Akt活化与淋巴结转移相关，但在AC中与rS6活化相关，在SCC中与mTOR活化相关。总之，（i）EGFR/Akt/mTOR通路的组成性激活存在于确定的NSCLC亚组中;（ii）mTOR/S6 K/rS6轴在AC中频繁激活，即使在SCC中，也通过EGFR突变通过Akt组成性激活;（iii）mTOR和rS6分别是SCC和AC中淋巴结转移的可能决定因素。(C)2011 Elsevier Inc. All rights reserved.
The expression/activation of epidermal growth factor receptor (EGFR) and the correlation with the phosphorylation status of downstream modulator proteins, Akt, mammalian target of rapamycin (mTOR), p70S6-kinase (S6K), ribosomal protein S6 (rS6), and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), were analyzed and EGFR/Akt signaling was evaluated in lung carcinomas. Immunohistochemical analysis of 140 cases revealed overexpression of EGFR in 37.9% and phosphorylation in 37.1%, but much less in small cell carcinoma. Combined analysis with immunoblotting revealed that when EGFR is activated, at least one of the mTOR/S6K or mTOR/4E-BPI cascades was activated in 60% of the cases. Furthermore, constitutive activation of EGFR-Akt-mTOR was found in 17.9% of nonsmall cell lung carcinomas (NSCLCs). For each protein, the frequencies of the activation vary among histologic types. In adenocarcinoma (AC), 90% revealed mTOR activation regardless of EGFR status, and 60% of these showed activation of downstream S6K/rS6. Furthermore, mutation of EGFR was frequently accompanied by phosphorylation of EGFR and constitutive activation of entire EGFR through rS6 was observed in 50% of carcinoma harboring EGFR mutation, including squamous cell carcinoma (SCC). By clinicopathologic analysis, Akt activation was correlated with lymph node metastasis in general, but nodal metastasis was correlated with rS6 activation in AC and with mTOR activation in SCC. In conclusion, (i) constitutive activation of EGFR/Akt/mTOR pathway was present in defined subset of NSCLC; (ii) mTOR/S6K/rS6 axis is frequently activated in AC, and constitutively activated through Akt by EGFR mutation even in SCC; and (iii) mTOR and rS6 are possible determinants of nodal metastasis in SCC and AC, respectively. (C) 2011 Elsevier Inc. All rights reserved.