Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5-lipoxygenase expression in aggressive subtypes of endometrial cancer:Eicosanoid metabolism in endometrial cancer
| Autor: | A Wright, Anna Nicolaou, Sam Saidi, Sarika Munot, Georgia Mappa, T Broadhead, Stuart Barber, Richard Hutson, Karen A. Massey, Nafisa Wilkinson, Nicolas M. Orsi, David Nugent, Michele Cummings |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
ResearchInstitutes_Networks_Beacons/MICRA Lydia Becker Institute Inflammation medicine.disease_cause eicosanoids Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation Gene expression Lipidomics medicine endometrium Tissue homeostasis Laser capture microdissection biology COX 15-PGDH LOX 15-hydroxyprostaglandin dehydrogenase cyclooxygenase 030104 developmental biology Eicosanoid Manchester Institute for Collaborative Research on Ageing 030220 oncology & carcinogenesis Arachidonate 5-lipoxygenase endometrial cancer Cancer research biology.protein 5-lipoxygenase gene expression lipidomics lipids (amino acids peptides and proteins) medicine.symptom Carcinogenesis prognostic |
| Zdroj: | Cummings, M, Massey, K A, Mappa, G, Wilkinson, N, Hutson, R, Munot, S, Saidi, S, Nugent, D, Broadhead, T, Wright, A I, Barber, S, Nicolaou, A & Orsi, N M 2019, ' Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5-lipoxygenase expression in aggressive subtypes of endometrial cancer : Eicosanoid metabolism in endometrial cancer ', The Journal of pathology, vol. 247, no. 1, pp. 21-34 . https://doi.org/10.1002/path.5160 |
| DOI: | 10.1002/path.5160 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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