Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer.
Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer.
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发表时间：
2005
期刊：
影响因子：
11.2
通讯作者：
R. P. Regala;Capella R. Weems;L. Jamieson;A. Khoor;E. Edell;C. Lohse;A. Fields
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文献类型：
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作者：
R. P. Regala;Capella R. Weems;L. Jamieson;A. Khoor;E. Edell;C. Lohse;A. Fields
蛋白激酶C （PKC）同工酶长期以来被认为与癌变有关。然而，人们对这些酶在人类癌症中的功能意义知之甚少。我们最近发现非典型PKC （aPKC）同工酶PKCiota在人非小细胞肺癌（NSCLC）细胞中过表达，PKCiota在人肺腺癌A549细胞系的体外转化生长和体内致瘤性中起关键作用。基于以下标准，我们提供了令人信服的证据，证明PKCiota是非小细胞肺癌的致癌基因：(a) aPKCiota在绝大多数原发性非小细胞肺癌肿瘤中过表达；(b)肿瘤PKCiota表达水平预测NSCLC患者的不良生存率；PKCiota基因在已建立的非小细胞肺癌细胞系和原发性非小细胞肺癌肿瘤中经常扩增；(d)基因扩增驱动PKCiota在NSCLC细胞系和原发性NSCLC肿瘤中的表达；(e)以显性阴性PKCiota等位基因破坏PKCiota信号传导，可阻断携带PKCiota基因扩增的人NSCLC细胞的转化生长。综上所述，我们的数据提供了确凿的证据，证明PKCiota是NSCLC细胞转化生长所必需的，PKCiota基因是通过扩增进行肿瘤特异性遗传改变的靶标。有趣的是，PKCiota表达预测非小细胞肺癌患者的生存率较低，与肿瘤分期无关。因此，PKCiota表达谱可能有助于识别复发风险较高的早期NSCLC患者。我们的功能数据表明，PKCiota是一个有吸引力的靶点，用于开发新的、基于机制的治疗方法来治疗非小细胞肺癌。
Protein kinase C (PKC) isozymes have long been implicated in carcinogenesis. However, little is known about the functional significance of these enzymes in human cancer. We recently showed that the atypical PKC (aPKC) isozyme PKCiota is overexpressed in human non-small cell lung cancer (NSCLC) cells and that PKCiota plays a critical role in the transformed growth of the human lung adenocarcinoma A549 cell line in vitro and tumorigenicity in vivo. Here we provide compelling evidence that PKCiota is an oncogene in NSCLC based on the following criteria: (a) aPKCiota is overexpressed in the vast majority of primary NSCLC tumors; (b) tumor PKCiota expression levels predict poor survival in patients with NSCLC; (c) the PKCiota gene is frequently amplified in established NSCLC cell lines and primary NSCLC tumors; (d) gene amplification drives PKCiota expression in NSCLC cell lines and primary NSCLC tumors; and (e) disruption of PKCiota signaling with a dominant negative PKCiota allele blocks the transformed growth of human NSCLC cells harboring PKCiota gene amplification. Taken together, our data provide conclusive evidence that PKCiota is required for the transformed growth of NSCLC cells and that the PKCiota gene is a target for tumor-specific genetic alteration by amplification. Interestingly, PKCiota expression predicts poor survival in NSCLC patients independent of tumor stage. Therefore, PKCiota expression profiling may be useful in identifying early-stage NSCLC patients at elevated risk of relapse. Our functional data indicate that PKCiota is an attractive target for development of novel, mechanism-based therapeutics to treat NSCLC.