Cummings, M, Massey, KA, Mappa, G et al. (10 more authors) (2018) Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer. Journal of Pathology, 247 (1). pp. 21-34. ISSN 0022-3417
Abstract
Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX‐2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis, to integrate these with eicosanoid profiles in matched clinical specimens and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography‐tandem mass spectrometry in fresh frozen normal, hyperplastic and cancerous (Types I and II) endometrial specimens (n=192). Sample‐matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX‐2 mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE₂/PGF₂α inactivation via 15‐hydroxyprostaglandin dehydrogenase (HPGD) in Type II ECs. Increased expression of 5‐lipoxygenase (ALOX5) mRNA was also identified in Type II ECs, together with proportional increases in its product, 5‐hydroxyeicosatetraenioic acid (5‐HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n=419). While neither COX‐1 nor COX‐2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression associated with the worst overall and progression‐free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. This is an author produced version of a paper published in Journal of Pathology. Uploaded in accordance with the publisher's self-archiving policy. This article may be used for non-commercial purposes in accordance with the Wiley Terms and Conditions for Self-Archiving. |
Keywords: | lipidomics; eicosanoids; gene expression; endometrial cancer; cyclooxygenase; COX; LOX; 5-lipoxygenase; 15-PGDH; 15-hydroxyprostaglandin dehydrogenase; prognostic; endometrium |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Mathematics (Leeds) > Statistics (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Obstetrics & Gynaecology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Pathology & Tumour Biology (Leeds) |
Funding Information: | Funder Grant number Wellbeing of Women RG1210 Yorkshire Cancer Research LPP053 |
Depositing User: | Symplectic Publications |
Date Deposited: | 31 Aug 2018 10:44 |
Last Modified: | 31 Aug 2019 00:41 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/path.5160 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:135138 |