Astrocyte-derived CCL20 reinforces HIF-1-mediated hypoxic responses in glioblastoma by stimulating the CCR6-NF-κB signaling pathway
Astrocyte-derived CCL20 reinforces HIF-1-mediated hypoxic responses in glioblastoma by stimulating the CCR6-NF-κB signaling pathway
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DOI：
10.1038/s41388-018-0182-7
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发表时间：
2018-06-01
期刊：
影响因子：
8
通讯作者：
Park, Jong-Wan
中科院分区：
文献类型：
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作者：
Jin, Peng;Shin, Seung-Hyun;Park, Jong-Wan
在肿瘤发展过程中，基质细胞被选入肿瘤环境并为肿瘤提供有利条件。缺氧通过激活缺氧诱导因子1（HIF-1）刺激癌细胞获得更恶性的表型。鉴于胶质母细胞瘤中的癌细胞和星形胶质细胞在缺氧微环境中共存，我们研究了星形胶质细胞是否影响胶质母细胞瘤细胞对缺氧的适应。免疫印迹，报告分析，定量RT-PCR，染色质免疫沉淀进行评估胶质母细胞瘤细胞中的HIF-1信号。使用细胞因子阵列鉴定星形胶质细胞衍生的趋化因子C-C基序配体20（CCL 20），并在原位异种移植物中评价其在胶质母细胞瘤发展中的作用。星形胶质细胞增加胶质母细胞瘤细胞缺氧时HIF-1 α的表达。HIF-1下游基因的表达，癌集落形成和胶质母细胞瘤细胞的Matrigel侵袭被预暴露于缺氧的星形胶质细胞的条件培养基刺激。CCL 20以缺氧依赖的方式从星形胶质细胞中分泌，并破坏胶质母细胞瘤细胞中HIF-1 α的缺氧诱导。从机制上讲，CCL 20/CCR 6信号通路通过刺激核因子κ B驱动的HIF 1A基因的反式激活上调HIF-1 α。与对照肿瘤相比，CCR 6缺陷的胶质母细胞瘤异种移植物生长更慢，血管化较差，并且表达较低水平的HIF-1 α及其下游蛋白。此外，在来自人胶质母细胞瘤组织的GEO和TCGA数据集中，CCR 6表达与HIF-1 α表达相关。这些结果表明，胶质母细胞瘤细胞很好地适应缺氧应激凭借的CCL 20来自相邻的星形胶质细胞。
During tumor development, stromal cells are co-opted to the tumor milieu and provide favorable conditions for the tumor. Hypoxia stimulates cancer cells to acquire a more malignant phenotype via activation of hypoxia-inducible factor 1 (HIF-1). Given that cancer cells and astrocytes in glioblastomas coexist in a hypoxic microenvironment, we examined whether astrocytes affect the adaptation of glioblastoma cells to hypoxia. Immunoblotting, reporter assays, quantitative RT-PCR, and chromatin immunoprecipitation were performed to evaluate HIF-1 signaling in glioblastoma cells. Astrocyte-derived chemokine C-C motif ligand 20 (CCL20) was identified using cytokine arrays, and its role in glioblastoma development was evaluated in orthotopic xenografts. Astrocytes augmented HIF-1 alpha expression in glioblastoma cells under hypoxia. The expression of HIF-1 downstream genes, cancer colony formation, and Matrigel invasion of glioblastoma cells were stimulated by conditioned medium from astrocytes pre-exposed to hypoxia. CCL20 was secreted in a hypoxia-dependent manner from astrocytes and busted the hypoxic induction of HIF-1 alpha in glioblastoma cells. Mechanistically, the CCL20/CCR6 signaling pathway upregulates HIF-1 alpha by stimulating nuclear factor kappa B-driven transactivation of the HIF1A gene. Compared with the control tumors, CCR6-deficient glioblastoma xenografts grew more slowly, with poor vascularization, and expressed lower levels of HIF-1 alpha and its downstream proteins. Furthermore, CCR6 expression was correlated with HIF-1 alpha expression in GEO and TCGA datasets from human glioblastoma tissues. These results suggest that glioblastoma cells adapt well to hypoxic stress by virtue of CCL20 derived from neighboring astrocytes.