Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC G1V 4G5, Canada.
Centenary Institute, University of Sydney, Camperdown, NSW 2006, Australia.
J Lipid Res. 2019 Oct;60(10):1776-1786. doi: 10.1194/jlr.M093955. Epub 2019 Aug 13.
Lung cancer causes more deaths than any other cancer. Sphingolipids encompass metabolically interconnected species whose balance has pivotal effects on proliferation, migration, and apoptosis. In this study, we paralleled quantification of sphingolipid species with quantitative (q)PCR analyses of metabolic enzymes in order to identify dysregulated routes of sphingolipid metabolism in different subtypes of lung cancers. Lung samples were submitted to histopathological reexamination in order to confirm cancer type/subtype, which included adenocarcinoma histological subtypes and squamous cell and neuroendocrine carcinomas. Compared with benign lesions and tumor-free parenchyma, all cancers featured decreased sphingosine-1-phosphate and SMs. qPCR analyses evidenced differential mechanisms leading to these alterations between cancer types, with neuroendocrine carcinomas upregulating , but being downregulated in adenocarcinomas and squamous cell carcinomas. 2-Hydroxyhexosylceramides (2-hydroxyHexCers) were specifically increased in adenocarcinomas. While UDP-glycosyltransferase 8 () transcript levels were increased in all cancer subtypes, fatty acid 2-hydroxylase () levels were higher in adenocarcinomas than in squamous and neuroendocrine carcinomas. As a whole, we report differing mechanisms through which all forms of lung cancer achieve low SM and lysosphingolipids. Our results also demonstrate that upregulation is required for the accumulation of 2-hydroxyHexCers in lung cancers featuring high levels of .
肺癌导致的死亡人数超过其他任何癌症。神经鞘脂类包含代谢相互关联的物种，其平衡对增殖、迁移和细胞凋亡有重要影响。在这项研究中，我们平行定量了神经鞘脂类物种，并对代谢酶进行了定量（q）PCR 分析，以确定不同类型肺癌中神经鞘脂代谢失调的途径。为了确认癌症的类型/亚型，对肺组织样本进行了组织病理学重新检查，其中包括腺癌的组织学亚型以及鳞状细胞癌和神经内分泌癌。与良性病变和无肿瘤的肺实质相比，所有癌症的神经鞘氨醇-1-磷酸和 SM 都减少了。qPCR 分析表明，不同类型的癌症之间导致这些变化的机制不同，神经内分泌癌上调，但腺癌和鳞状细胞癌下调。2-羟己糖神经酰胺（2-hydroxyHexCers）在腺癌中特异性增加。虽然所有癌症亚型的 UDP-糖基转移酶 8（）转录本水平均增加，但与鳞状细胞癌和神经内分泌癌相比，腺癌中脂肪酸 2-羟化酶（）水平更高。总的来说，我们报告了所有类型的肺癌通过不同的机制实现低 SM 和溶血神经鞘脂的积累。我们的研究结果还表明，在高水平的情况下，上调是导致肺癌中 2-hydroxyHexCers 积累的必需条件。
