肺癌中 NF-κB 通路激活的一个关键机制是 KEAP1/CUL3 E3 泛素连接酶复合物成分的遗传破坏。
Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation in lung cancer.
机构信息
Integrative Oncology Department, BC Cancer Research Centre, Vancouver, Canada.
出版信息
J Thorac Oncol. 2011 Sep;6(9):1521-9. doi: 10.1097/JTO.0b013e3182289479.
INTRODUCTION
Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB) (IKK-β/IKK-2), which activates NF-κB, is a substrate of the KEAP1-CUL3-RBX1 E3-ubiquitin ligase complex, implicating this complex in NF-κB pathway regulation. We investigated complex component gene disruption as a novel genetic mechanism of NF-κB activation in non-small cell lung cancer.
METHODS
A total of 644 tumor- and 90 cell-line genomes were analyzed for gene dosage status of the individual complex components and IKBKB. Gene expression of these genes and NF-κB target genes were analyzed in 48 tumors. IKBKB protein levels were assessed in tumors with and without complex or IKBKB genetic disruption. Complex component knockdown was performed to assess effects of the E3-ligase complex on IKBKB and NF-κB levels, and phenotypic importance of IKBKB expression was measured by pharmacological inhibition.
RESULTS
We observed strikingly frequent genetic disruption (42%) and aberrant expression (63%) of the E3-ligase complex and IKBKB in the samples examined. Although both adenocarcinomas and squamous cell carcinomas showed complex disruption, the patterns of gene disruption differed. IKBKB levels were elevated with complex disruption, knockdown of complex components increased activated forms of IKBKB and NF-κB proteins, and IKBKB inhibition detriments cell viability, highlighting the biological significance of complex disruption. NF-κB target genes were overexpressed in samples with complex disruption, further demonstrating the effect of complex disruption on NF-κB activity.
CONCLUSIONS
Gene dosage alteration is a prominent mechanism that disrupts each component of the KEAP1-CUL3-RBX1 complex and its NF-κB stimulating substrate, IKBKB. Herein, we show that, multiple component disruption of this complex represents a novel mechanism of NF-κB activation in non-small cell lung cancer.
简介
B 细胞κ轻肽基因增强子核因子κB 抑制物激酶β（IKBKB）（IKK-β/IKK-2）可激活 NF-κB，是 KEAP1-CUL3-RBX1 E3 泛素连接酶复合物的底物，表明该复合物参与 NF-κB 通路的调节。我们研究了非小细胞肺癌中 NF-κB 激活的新型遗传机制，即抑制复合物成分基因缺失。
方法
分析了 644 例肿瘤和 90 例细胞系基因组中单个复合物成分和 IKBKB 的基因剂量状态。对 48 例肿瘤的这些基因和 NF-κB 靶基因的表达进行了分析。评估了有或无复合物或 IKBKB 遗传缺失的肿瘤中的 IKBKB 蛋白水平。进行了复合物成分敲低，以评估 E3 连接酶复合物对 IKBKB 和 NF-κB 水平的影响，并通过药理学抑制法测量 IKBKB 表达的表型重要性。
结果
在所检查的样本中，我们观察到 E3 连接酶复合物和 IKBKB 的遗传缺失（42%）和异常表达（63%）非常频繁。虽然腺癌和鳞状细胞癌均显示复合物缺失，但基因缺失模式不同。IKBKB 水平随着复合物缺失而升高，复合物成分的敲低增加了 IKBKB 和 NF-κB 蛋白的激活形式，而 IKBKB 抑制损害细胞活力，突出了复合物缺失的生物学意义。复合物缺失的样本中 NF-κB 靶基因过度表达，进一步证明了复合物缺失对 NF-κB 活性的影响。
结论
基因剂量改变是破坏 KEAP1-CUL3-RBX1 复合物及其 NF-κB 刺激底物 IKBKB 的每个成分的突出机制。在此，我们表明，该复合物的多个成分缺失代表了非小细胞肺癌中 NF-κB 激活的新机制。
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