齐留顿
卵巢癌
生物
下调和上调
花生四烯酸5-脂氧合酶
癌症研究
肿瘤坏死因子α
转移
肿瘤相关巨噬细胞
肿瘤进展
花生四烯酸
基质金属蛋白酶
癌症
肿瘤微环境
免疫学
酶
生物化学
基因
遗传学
肿瘤细胞
作者
Zhipeng Wen,H Liu,M Li,B Li,Wei Gao,Qianqian Shao,Bin Fan,Fen Zhao,Q Wang,Qi Xie,Yue Yang,Jiangtao Yu,Xun Qu
出处
期刊:Oncogene
[Springer Nature]
日期:2014-03-24
卷期号:34 (10): 1241-1252
被引量:78
摘要
5-lipoxygenase (5-LOX), a member of the lipoxygenase gene family, is a key enzyme assisting in the conversion of arachidonic acid to 5-HETE and leukotrienes. Tumor-associated macrophages (TAMs) have a critical role in the progression and metastasis of many tumors, including ovarian tumors. Moreover, TAMs are often found in a high density in the hypoxic areas of tumors. However, the relevant mechanisms have not been studied explicitly until now. In this study, we found that the expression of 5-LOX strongly correlated with the density of TAMs in hypoxic areas of human ovarian tumor tissues. In cultured ovarian cancer cells, 5-LOX metabolites were increased under hypoxic conditons. Increased 5-LOX metabolites from hypoxic ovarian cancer cells promoted migration and invasion of macrophages, which was further demonstrated to be mediated by the upregulation of matrix metalloproteinase (MMP)-7 expression through the p38 pathway. Besides, we also showed that 5-LOX metabolites enhanced the release of tumor necrosis factor (TNF-α) and heparin-binding epidermal growth factor-like growth factor through upregulation of MMP-7. Furthermore, in animal models, Zileuton (a selective and specific 5-LOX inhibitor) reduced the MMP-7 expression and the number of macrophages infiltrating in the xenograft. Our findings suggest for the first time that increased metabolites of 5-LOX from hypoxic ovarian cancer cells promote TAM infiltration. These results of this study have immediate translational implications for the therapeutic exploitation of TAMs.
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