Leukotriene Synthesis Is Critical for Medulloblastoma Progression
Leukotriene Synthesis Is Critical for Medulloblastoma Progression
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白三烯合成对于髓母细胞瘤进展至关重要
DOI：
10.1158/1078-0432.ccr-18-3549
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发表时间：
2019-11-01
影响因子：
11.5
通讯作者：
Yang, Zeng-Jie
中科院分区：
文献类型：
--
作者：
Du, Fang;Yuelling, Larra;Yang, Zeng-Jie
目的：在这里，我们研究了白三烯，众所周知的炎症介质，在刺猬通路相关的髓母细胞瘤的肿瘤发生中的作用，并测试了白三烯生物合成的拮抗剂在髓母细胞瘤治疗中的疗效。实验设计：我们通过ELISA检测髓母细胞瘤细胞中的白三烯水平。我们接下来测试了髓母细胞瘤细胞中白三烯的合成是否依赖于hedgehog通路的激活，或者星形胶质细胞分泌的hedgehog配体的存在。然后，我们研究了是否白三烯介导的刺猬诱导巢蛋白在肿瘤细胞中的表达。白三烯在髓母细胞瘤中肿瘤细胞增殖和肿瘤生长中的功能通过用shRNA敲低5-脂氧合酶（白三烯合成的关键酶）或使用5-脂氧合酶缺陷小鼠来确定。最后，在体内和体外测试了白三烯合成的拮抗剂在髓母细胞瘤治疗中的功效。结果：髓母细胞瘤细胞中白三烯表达明显上调。白三烯合成的增加依赖于星形胶质细胞分泌的hedgehog配体，这是髓母细胞瘤微环境的主要成分。白三烯刺激肿瘤细胞表达巢蛋白，一种髓母细胞瘤生长所必需的细胞骨架蛋白。基因阻断白三烯合成能显著抑制髓母细胞瘤细胞增殖和肿瘤生长。药物抑制白三烯的合成显着抑制髓母细胞瘤细胞的增殖，但对正常神经元祖细胞的增殖没有影响。此外，白三烯合成的拮抗剂对耐药髓母细胞瘤表现出有希望的肿瘤抑制功效。结论：我们的研究结果揭示了一种新的信号通路，这是至关重要的髓母细胞瘤细胞增殖和肿瘤进展，白三烯生物合成是一个有前途的治疗靶点髓母细胞瘤治疗。
Purpose: Here, we examined the role of leukotrienes, well-known inflammatory mediators, in the tumorigenesis of hedgehog pathway-associated medulloblastoma, and tested the efficacies of antagonists of leukotriene biosynthesis in medulloblastoma treatment. Experimental Design: We examined the leukotriene levels in medulloblastoma cells by ELISA. We next tested whether leukotriene synthesis in medulloblastoma cells relied on activation of hedgehog pathway, or the presence of hedgehog ligand secreted by astrocytes. We then investigated whether leukotriene mediated hedgehog-induced Nestin expression in tumor cells. The functions of leukotriene in tumor cell proliferation and tumor growth in medulloblastoma were determined through knocking down 5-lipoxygenase (a critical enzyme for leukotriene synthesis) by shRNAs, or using 5-lipoxygenase–deficient mice. Finally, the efficacies of antagonists of leukotriene synthesis in medulloblastoma treatment were tested in vivo and in vitro. Results: Leukotriene was significantly upregulated in medulloblastoma cells. Increased leukotriene synthesis relied on hedgehog ligand secreted by astrocytes, a major component of medulloblastoma microenvironment. Leukotriene stimulated tumor cells to express Nestin, a cytoskeletal protein essential for medulloblastoma growth. Genetic blockage of leukotriene synthesis dramatically suppressed medulloblastoma cell proliferation and tumor growth in vivo. Pharmaceutical inhibition of leukotriene synthesis markedly repressed medulloblastoma cell proliferation, but had no effect on proliferation of normal neuronal progenitors. Moreover, antagonists of leukotriene synthesis exhibited promising tumor inhibitory efficacies on drug-resistant medulloblastoma. Conclusions: Our findings reveal a novel signaling pathway that is critical for medulloblastoma cell proliferation and tumor progression, and that leukotriene biosynthesis represents a promising therapeutic target for medulloblastoma treatment.