LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT.
LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT.
复制标题
DOI：
10.1097/jto.0000000000000173
复制
发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Carbone DP
中科院分区：
文献类型：
--
作者：
Kaufman JM;Amann JM;Park K;Arasada RR;Li H;Shyr Y;Carbone DP
丝氨酸/苏氨酸激酶11（STK 11或LKB 1）的失活在肺癌中很常见，因此了解其通路和表型的改变将有助于靶向治疗策略的开发。研究了v-Ki-ras 2 Kirsten大鼠肉瘤病毒癌基因同源物（Kras）突变型肺癌小鼠模型中的基因和蛋白表达，以深入了解这些肿瘤的生物学。然而，LKB 1丢失在人肺癌中的分子后果尚未完全表征。我们研究了切除的肺腺癌、非小细胞肺癌细胞系和小鼠肿瘤中与LKB 1缺失相关的基因表达谱。使用基因集富集和转录因子分析以及与体细胞突变和蛋白质组学数据的整合来解释失调基因的生物学意义。LKB 1的缺失与切除的人肺癌和与小鼠模型显著不同的细胞系中一致的基因表达变化相关。我们的分析暗示了与LKB 1缺失相关的新的生物学特征，包括线粒体代谢的改变，kelch样ECH相关蛋白1（KEAP 1）突变激活核呼吸因子2（NRF 2）转录因子，以及磷脂酰肌醇3-激酶和v-akt小鼠胸腺瘤病毒癌基因同源物（PI 3 K/AKT）途径的衰减。此外，我们推导出一个16基因分类器，准确预测LKB 1突变和损失的非突变机制。在体外，将LKB 1转导到LKB 1突变细胞系中导致该特征的减弱。LKB 1的缺失定义了一个与特征性分子表型和独特基因表达特征相关的肺腺癌亚群。研究这些影响可能会提高我们对这些肿瘤生物学的理解，并导致靶向治疗策略的确定。
Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene and protein expressions in a murine model of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant lung cancer have been studied to gain insight into the biology of these tumors. However, the molecular consequences of LKB1 loss in human lung cancer have not been fully characterized. We studied gene expression profiles associated with LKB1 loss in resected lung adenocarcinomas, non–small-cell lung cancer cell lines, and murine tumors. The biological significance of dysregulated genes was interpreted using gene set enrichment and transcription factor analyses and also by integration with somatic mutations and proteomic data. Loss of LKB1 is associated with consistent gene expression changes in resected human lung cancers and cell lines that differ substantially from the mouse model. Our analysis implicates novel biological features associated with LKB1 loss, including altered mitochondrial metabolism, activation of the nuclear respiratory factor 2 (NRF2) transcription factor by kelch-like ECH-associated protein 1 (KEAP1) mutations, and attenuation of the phosphatidylinositiol 3-kinase and v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway. Furthermore, we derived a 16-gene classifier that accurately predicts LKB1 mutations and loss by nonmutational mechanisms. In vitro, transduction of LKB1 into LKB1-mutant cell lines results in attenuation of this signature. Loss of LKB1 defines a subset of lung adenocarcinomas associated with characteristic molecular phenotypes and distinctive gene expression features. Studying these effects may improve our understanding of the biology of these tumors and lead to the identification of targeted treatment strategies.