Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions
Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions
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DOI：
10.1093/carcin/bgh226
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发表时间：
2004-11-01
期刊：
影响因子：
4.7
通讯作者：
Testa, JR
中科院分区：
文献类型：
--
作者：
Balsara, BR;Pei, JM;Testa, JR
AKT在多种癌症中经常被激活，但其在肺肿瘤发生发展中的作用尚未得到很好的证实。我们利用组织芯片技术通过免疫组化检测了110例非小细胞肺癌（nsclc）中AKT的活性。在56例（51%）肿瘤中观察到AKT活化。为了进一步验证AKT通路的激活，我们检测了哺乳动物rapamycin靶点（mTOR）和forkhead靶点（FKHR）的磷酸化状态，这两个靶点是AKT的下游靶点。phospho-mTOR和phospho-FKHR分别在74%和68%的肿瘤中检测到阳性染色，并且与AKT的激活显著相关。磷酸化（活性）AKT阳性的肿瘤在低分期（I/II）和高分期（III/IV）肿瘤中出现的频率相似，这提高了AKT激活发生在肿瘤进展早期的可能性。因此，我们检测了12例肺癌高危患者的25个支气管上皮病变中AKT的活性。化生/发育不良区显示AKT活性，而正常和增生性支气管上皮很少或没有活性。由于一些支气管上皮病变可能发展为侵袭性癌症，我们使用体外细胞侵袭试验研究了AKT对肺癌细胞侵袭性的影响。转染野生型AKT的非小细胞肺癌细胞对肝细胞生长因子的侵袭性增强，而转染显性阴性AKT则消除了这种作用。总之，这些数据表明AKT激活在肺肿瘤发生中是一个频繁和早期的事件，这可能会增加恶性肿瘤进展的风险。因此，AKT代表了非小细胞肺癌高风险个体化学预防的潜在重要靶点。
AKT is frequently activated in various cancers, but its involvement in lung tumor development and progression is not well established. We examined AKT activity by immunohistochemistry in 110 non-small cell lung carcinomas (NSCLCs) using tissue microarrays. AKT activation was observed in 56 (51%) tumors. To further validate activation of the AKT pathway in this series, we examined the phosphorylation status of the mammalian target of rapamycin (mTOR) and forkhead (FKHR), two downstream targets of AKT. Positive staining for phospho-mTOR and phospho-FKHR were detected in 74% and 68% of tumors, respectively, and was significantly associated with activation of AKT. Tumors positive for phosphorylated (active) AKT were present with a similar frequency in low stage (I/II) and high stage (III/IV) tumors, raising the possibility that AKT activation occurs early in tumor progression. We therefore examined AKT activity in 25 bronchial epithelial lesions from 12 patients at high risk of lung cancer. Metaplastic/dysplastic areas showed AKT activity, whereas normal and hyperplastic bronchial epithelia exhibited little or no activity. Since some bronchial epithelial lesions may develop into invasive cancers, we examined the effect of AKT on invasiveness of lung cancer cells, using an in vitro cell invasion assay. Transfection of NSCLC cells with wild-type AKT increased invasiveness in response to hepatocyte growth factor, whereas transfection with dominant negative AKT abrogated this effect. Collectively, these data suggest that AKT activation is a frequent and early event in lung tumorigenesis, which may enhance risk of progression to malignancy. Thus, AKT represents a potentially important target for chemoprevention in individuals at high risk of NSCLC.