AMP-activated protein kinase (AMPK) is a critical sensor of energy status that coordinates cell growth with energy balance. In non-small cell lung cancer (NSCLC) the role of AMPKα is controversial and its contribution to lung carcinogenesis is not well-defined. Furthermore, it remains largely unknown whether long non-coding RNAs (lncRNAs) are involved in the regulation of AMPK-mediated pathways. Here, we found that loss of AMPKα in combination with activation of mutant KRAS^G12D increased lung tumour burden and reduced survival in Kras^LSLG12D/+/AMPKα^fl/fl mice. In agreement, functional in vitro studies revealed that AMPKα silencing increased growth and migration of NSCLC cells. In addition, we identified an AMPKα-modulated lncRNA, KIMAT1 (ENSG00000228709), which in turn regulates AMPKα activation by stabilizing the lactate dehydrogenase B (LDHB). Collectively, our study indicates that AMPKα loss promotes KRAS-mediated lung tumorigenesis and proposes a novel KRAS/KIMAT1/LDHB/AMPKα axis that could be exploited for therapeutic purposes.

AMP 活化蛋白激酶 (AMPK) 是能量状态的关键传感器，可协调细胞生长与能量平衡。在非小细胞肺癌 (NSCLC) 中，AMPKα 的作用存在争议，其对肺癌发生的贡献尚不明确。此外，长链非编码 RNA (lncRNA) 是否参与 AMPK 介导的通路的调控仍然很大程度上未知。在这里，我们发现 AMPKα 的缺失与突变体 KRAS ^G12D的激活相结合，增加了Kras ^LSLG12D/+ /AMPKα ^fl/fl小鼠的肺部肿瘤负荷并降低了存活率。同意，功能性体外研究表明，AMPKα 沉默会增加 NSCLC 细胞的生长和迁移。此外，我们还鉴定了一个 AMPKα 调节的 lncRNA，KIMAT1 (ENSG00000228709)，它反过来通过稳定乳酸脱氢酶 B (LDHB) 来调节 AMPKα 激活。总的来说，我们的研究表明 AMPKα 缺失促进了 KRAS 介导的肺肿瘤发生，并提出了一种可用于治疗目的的新型 KRAS/ KIMAT1 /LDHB/AMPKα 轴。