Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, ;Skåne University Hospital, Malmö, Sweden.
Division of Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Clinical Research Center, ;Skåne University Hospital, Malmö, Sweden; Section of Surgery, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Bayer HealthCare, Pharmaceuticals Medical Affairs, Solna, Sweden.
Exp Cell Res. 2014 Feb 15;321(2):255-66. doi: 10.1016/j.yexcr.2013.10.021. Epub 2013 Nov 5.
The abnormal activation of the Wnt/β-catenin pathway frequently occurs in colorectal cancer. The nuclear translocation of β-catenin activates the transcription of target genes that promote cell proliferation, survival, and invasion. The pro-inflammatory mediator leukotriene D4 (LTD4) exerts its effects through the CysLT1 receptor. We previously reported an upregulation of CysLT1R in patients with colon cancer, suggesting the importance of leukotrienes in colon cancer. The aim of this study was to investigate the impact of LTD4 on Wnt/β-catenin signaling and its effects on proliferation and migration of colon cancer cells. LTD4 stimulation led to an increase in β-catenin expression, β-catenin nuclear translocation and the subsequent transcription of MYC and CCND1. Furthermore, LTD4 significantly reduced the expression of E-cadherin and β-catenin at the plasma membrane and increased the migration and proliferation of HCT116 colon cancer cells. The effects of LTD4 can be blocked by the inhibition of CysLT1R. Furthermore, LTD4 induced the inhibition of glycogen synthase kinase 3 (GSK)-3β activity, indicating a crosstalk between the G-protein-coupled receptor CysLT1 and the Wnt/β-catenin pathway. In conclusion, LTD4, which can be secreted from macrophages and leukocytes in the tumor microenvironment, induces β-catenin translocation and the activation of β-catenin target genes, resulting in the increased proliferation and migration of colon cancer cells.
Wnt/β-catenin 通路的异常激活常发生在结直肠癌中。β-catenin 的核转位激活促进细胞增殖、存活和侵袭的靶基因转录。促炎介质白三烯 D4（LTD4）通过 CysLT1 受体发挥作用。我们之前报道过结肠癌患者 CysLT1R 的上调，表明白三烯在结肠癌中的重要性。本研究旨在研究 LTD4 对 Wnt/β-catenin 信号的影响及其对结肠癌细胞增殖和迁移的影响。LTD4 刺激导致 β-catenin 表达增加，β-catenin 核易位，随后 MYC 和 CCND1 的转录。此外，LTD4 显著降低了 HCT116 结肠癌细胞质膜上的 E-钙粘蛋白和 β-catenin 的表达，并增加了其迁移和增殖。LTD4 的作用可被 CysLT1R 抑制阻断。此外，LTD4 诱导糖原合酶激酶 3（GSK-3β）活性的抑制，表明 G 蛋白偶联受体 CysLT1 和 Wnt/β-catenin 通路之间存在串扰。总之，LTD4 可由肿瘤微环境中的巨噬细胞和白细胞分泌，诱导 β-catenin 易位和 β-catenin 靶基因的激活，导致结肠癌细胞增殖和迁移增加。
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