Department of Respiratory Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical School, Shanghai, China.
Cell Biol Toxicol. 2021 Feb;37(1):15-34. doi: 10.1007/s10565-020-09520-w. Epub 2020 Apr 28.
Lung cancer is a heterogeneous and complex disease with the highest incidence and mortality rate. The present study aims at defining the lung cancer phenome specificity of lipidomic profiles, screening target lipid-dependent transcriptional alternations, identifying target lipid-associated target genes, and exploring molecular mechanisms. Lung cancer-specific and lung cancer subtype-specific target lipids palmitic acid (C16:0) and stearic acid (C18:0) were found as target lipids by integrating clinical phenomics, lipidomics, and transcriptomics and exhibited antiproliferative effects in sensitive cells. The metabolism-associated gene ACSL5 or inflammation-associated gene CCL3 was identified in lung adenocarcinoma or small lung cancer cells, respectively. C16:0 or C18:0 could upregulate ACSL5 or CSF2 expression in a time- and dose-dependent pattern, and the deletion of both genes led to the insensitivity of cells. Target lipids increased the expression of PDK4 gene in different patterns and inhibited cell proliferation through alterations of intracellular energy. Thus, our data provide a new strategy to investigate the trans-points between clinical and phenomics and lipidomics and target lipid-associated molecular mechanisms to benefit from the discovery of new therapies.
肺癌是一种异质性和复杂性疾病，其发病率和死亡率最高。本研究旨在定义脂质组学谱的肺癌表型特异性，筛选靶脂质依赖性转录变化，鉴定靶脂质相关靶基因，并探讨分子机制。通过整合临床表型组学、脂质组学和转录组学，发现了特定于肺癌的靶脂质棕榈酸（C16:0）和硬脂酸（C18:0），并在敏感细胞中表现出抗增殖作用。在肺腺癌或小肺癌细胞中分别鉴定出与代谢相关的基因 ACSL5 或与炎症相关的基因 CCL3。C16:0 或 C18:0 可以以时间和剂量依赖的方式上调 ACSL5 或 CSF2 的表达，并且这两个基因的缺失导致细胞不敏感。靶脂质以不同的方式增加 PDK4 基因的表达，并通过改变细胞内能量来抑制细胞增殖。因此，我们的数据为研究临床表型组学和脂质组学与靶脂质相关分子机制之间的转点提供了一种新策略，有助于发现新的治疗方法。
