Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages.
Hepatocellular carcinoma progression promoted by 5-lipoxygenase activity in CD163(+) tumor-associated macrophages.
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DOI：
10.1016/j.biopha.2023.114592
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发表时间：
2023-03
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通讯作者：
Takuto Nosaka;Y. Murata;Kazuto Takahashi;Tatsushi Naito;Kazuya Ofuji;Hidetaka Matsuda;M. Ohtani;K. Hiramatsu;Y. Imamura;T. Goi;Y. Nakamoto
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作者：
Takuto Nosaka;Y. Murata;Kazuto Takahashi;Tatsushi Naito;Kazuya Ofuji;Hidetaka Matsuda;M. Ohtani;K. Hiramatsu;Y. Imamura;T. Goi;Y. Nakamoto
花生四烯酸5-脂氧合酶（5-LOX）是一种合成白三烯（LT）的酶，参与肿瘤的发生，包括增殖、侵袭、转移和耐药性。然而，5-LOX在肝细胞癌（HCC）中的功能作用仍有待阐明。在这项研究中，我们分析了5-LOX在HCC进展中的作用，并研究了靶向治疗的潜力。对86例切除的HCC标本和来自The Cancer Genome Atlas Liver Hepatocellular Carcinoma数据集的362例肝癌患者的临床数据的分析显示，5-LOX表达与术后生存相关。CD 163（+）肿瘤相关巨噬细胞（TAMs）中5-LOX水平与肿瘤增殖和干细胞潜能相关。在HCC小鼠模型中，CD 163（+）TAM表达5-LOX并产生LTB 4和LTC/D/E4; 5-LOX抑制剂齐留通抑制HCC进展。LTB 4和LTC/D/E4通过细胞外信号调节激酶1/2和干细胞相关基因的磷酸化促进癌症增殖和干细胞能力。总之，我们确定了一种新的HCC进展机制，其中CD 163（+）TAM表达5-LOX并产生LTB 4和LTC/D/E4，从而增强HCC细胞的增殖和干细胞潜能。此外，5-LOX活性的抑制调节HCC进展，表明其具有作为新的治疗靶点的潜力。
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.