Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer
Myc linked to dysregulation of cholesterol transport and storage in nonsmall cell lung cancer
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DOI：
10.1194/jlr.ra120000899
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发表时间：
2020-11-01
影响因子：
6.5
通讯作者：
Griffin, Julian L.
中科院分区：
文献类型：
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作者：
Hall, Zoe;Wilson, Catherine H.;Griffin, Julian L.
非小细胞肺癌（NSCLC）是癌症相关死亡的主要原因。虽然Kras突变和Myc过表达在患者中很常见，但对脂质代谢改变在肺癌中的作用及其与致癌Myc的相互作用知之甚少。在这里，我们使用一个转基因小鼠模型的Kras驱动的肺腺癌与可逆激活的Myc结合表面分析，肺肿瘤和转录组学的脂质分析，以研究Myc活性对胆固醇稳态的影响。我们的研究结果表明，Myc的激活导致胆固醇酯（CE）储存在脂滴的积累。随后的Myc失活导致CE进一步增加，与Myc从未被激活的肿瘤相反。基因表达分析将胆固醇转运和储存途径与Myc活性联系起来。我们的研究结果表明，Myc活性增加与胆固醇流入增加，流出减少，以及在肺肿瘤中富含CE的脂滴的积累有关。靶向胆固醇稳态被认为是探索肺癌新疗法的一种有前景的途径，在人类NSCLC中具有诊断和分层潜力。
Nonsmall cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. While mutations in Kras and overexpression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc combined with surface analysis lipid profiling of lung tumors and transcriptomics to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that the activation of Myc leads to the accumulation of cholesteryl esters (CEs) stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumors in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux, and accumulation of CE-rich lipid droplets in lung tumors. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.