Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages.

Autor: Nosaka T; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Murata Y; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Takahashi K; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Naito T; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Ofuji K; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Matsuda H; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Ohtani M; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Hiramatsu K; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Imamura Y; Division of Diagnostic Pathology/Surgical Pathology, University of Fukui Hospital, Fukui, Japan., Goi T; First Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan., Nakamoto Y; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan. Electronic address: nakamoto-med2@med.u-fukui.ac.jp.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Jun; Vol. 162, pp. 114592. Date of Electronic Publication: 2023 Mar 24.
DOI: 10.1016/j.biopha.2023.114592
Abstrakt: Arachidonic acid 5-lipoxygenase (5-LOX), an enzyme that synthesizes leukotrienes (LTs), is involved in cancer development including proliferation, invasion, metastasis and drug resistance. However, the functional role of 5-LOX in hepatocellular carcinoma (HCC) remains to be elucidated. In this study, we analyzed the contribution of 5-LOX in HCC progression and investigated the potential of targeted therapy. Analysis of 86 resected HCC specimens and the clinical data of 362 cases of liver cancer from The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset, showed that 5-LOX expression was associated with postoperative survival. The cancer proliferative and stem cell potential were correlated with the levels of 5-LOX in CD163(+) tumor-associated macrophages (TAMs). In an HCC mouse model, CD163(+) TAMs expressed 5-LOX and produced LTB4 and LTC/D/E4; the 5-LOX inhibitor, zileuton, suppressed HCC progression. LTB4 and LTC/D/E4 promoted cancer proliferation and stem cell capacity via phosphorylation of extracellular signal-regulated kinase 1/2 and stem cell-associated genes. Taken together, we identified a novel mechanism of HCC progression in which CD163(+) TAMs express 5-LOX and produce LTB4 and LTC/D/E4, thereby enhancing the proliferative and stem cell potential of HCC cells. Furthermore, inhibition of 5-LOX activity regulates HCC progression, suggesting it has potential as a new therapeutic target.
Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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