Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu ) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.

中文翻译：

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IKKα 失活通过破坏主要的氧化还原调节途径促进 Kras 引发的肺腺癌的发展。


肺腺癌（ADC）和鳞状细胞癌（SCC）是两种不同且主要的人类肺癌类型。 IκB 激酶 α (IKKα) 已被证明可以抑制肺 SCC 的发展，但其在 ADC 中的作用尚不清楚。我们在人肺 ADC 的编码 IKKα 的 CHUK 基因座中发现了失活突变和同源或半合子缺失。 CHUK 缺失显着缩短了携带 KRAS 突变的肺部 ADC 患者的生存时间。在小鼠中，肺特异性 Ikkα 消融 (IkkαΔLu ) 诱导自发 ADC 并促进 KrasG12D 启动的 ADC 发育，同时伴有细胞增殖增加、细胞衰老减少和活性氧 (ROS) 积累。 IKKα 缺失上调 NOX2 并下调 NRF2，导致 ROS 积累并阻断细胞衰老诱导，共同加速 ADC 的发育。 NADPH 氧化酶或 ROS 的药理学抑制会损害 IkkαΔLu 小鼠中 KrasG12D 介导的 ADC 发育。因此，IKKα 通过控制氧化还原调节途径来调节肺 ADC 的发育。这项研究表明，IKKα 通过调节肿瘤细胞相关 ROS 代谢的独特机制，在人和小鼠中充当肺 ADC 的抑制剂。