High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma

High FA2H and UGT8 transcript levels predict hydroxylated hexosylceramide accumulation in lung adenocarcinoma.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1194/jlr.M093955
Journal or Publication Title: Journal of Lipid Research
Volume: 60
Number: 10
Page Range: pp. 1776-1786
Date: 2019
Divisions: Lipid Metabolism and Neurochemistry
Depositing User: General Admin
Identification Number: 10.1194/jlr.M093955
ISSN: 0022-2275
Date Deposited: 21 Dec 2020 23:22

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.

Keywords: 2-hydroxyhexosylceramide; cancer; fatty acid 2-hydroxylase; fatty acids; gene expression; mass spectrometry; neuroendocrine; sphingolipid; squamous; uridine 5′-diphosphate-glycosyltransferase 8.

Copyright © 2019 Lemay et al.

Lemay, Anne-Marie
Courtemanche, Olivier
Couttas, Timothy A.
Jamsari, Giuleta
Gagné, Andréanne
Bossé, Yohan
Joubert, Philippe
Don, Anthony S.
Marsolais, David
Last Modified: 21 Dec 2020 23:22
URI: https://eprints.centenary.org.au/id/eprint/144

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