期刊
JOURNAL OF LIPID RESEARCH
卷 60, 期 10, 页码 1776-1786出版社
ELSEVIER
DOI: 10.1194/jlr.M093955
关键词
2-hydroxyhexosylceramide; sphingolipid; squamous; neuroendocrine; cancer; fatty acids; gene expression; mass spectrometry; fatty acid 2-hydroxylase; uridine 5 '-diphosphate-glycosyltransferase 8
资金
- Cancer Research Society [22339]
- Faculty of Medicine of Universite Laval
- Fonds de Recherche du Quebec J2 scholarship
- Canada Research Chair in Genomics of Heart and Lung Diseases
- National Health and Medical Research Council/Australian Research Council Dementia Research Fellowship [1110400]
- National Health and Medical Research Council [1100626]
- National Health and Medical Research Council of Australia [1100626, 1110400] Funding Source: NHMRC
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 SGPL1, but CERT1 being downregulated in adenocarcinomas and squamous cell carcinomas. 2-Hydroxyhexosylceramides (2-hydroxyHexCers) were specifically increased in adenocarcinomas. While UDP-glycosyltransferase 8 (UGT8) transcript levels were increased in all cancer subtypes, fatty acid 2-hydroxylase (FA2H) 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 FA2H upregulation is required for the accumulation of 2-hydroxyHexCers in lung cancers featuring high levels of UGT8.
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