Selective upregulation of interleukin-8 by human rhabdomyosarcomas in response to hypoxia: therapeutic implications.
Selective upregulation of interleukin-8 by human rhabdomyosarcomas in response to hypoxia: therapeutic implications.
复制标题
人横纹肌肉瘤响应缺氧选择性上调白细胞介素 8：治疗意义。
DOI：
10.1002/ijc.24732
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发表时间：
2010
影响因子：
6.4
通讯作者：
Ratajczak,MariuszZ
中科院分区：
文献类型：
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作者：
Wysoczynski,Marcin;Shin,Dong-Myung;Kucia,Magda;Ratajczak,MariuszZ
横纹肌肉瘤（RMS）是青少年和儿童最常见的软组织肉瘤。由于RMS肿瘤高度血管化，我们试图确定RMS细胞分泌的哪些因子在刺激缺氧引起的血管生成中至关重要。为了解决这个问题，我们在正常稳态和缺氧条件下评估了8种人RMS细胞系中几种促血管生成因子[白细胞介素（IL）-8、血管内皮生长因子（VEGF）、成纤维细胞生长因子（FGF）-2、基质衍生因子（SDF）-1、肝细胞生长因子（HGF）和白血病抑制因子（LIF）]的表达。我们通过真实的实时定量聚合酶链反应（RQ-PCR）发现并通过酶联免疫吸附测定（ELISA）证实，在评估的所有因素中，在常氧条件下表达非常低的IL-8在低氧条件下由RMS细胞系非常高地表达和分泌（约40-170倍）。有趣的是，这种上调不受敲低缺氧诱导因子（HIF）-1 α的影响，但受到丝裂原活化蛋白激酶（MAPK）p42/44和磷脂酰肌醇3激酶（PI 3 K）/AKT通路抑制剂的抑制。这表明IL-8表达以活化蛋白（AP）-1-和核因子（NF）-κB-依赖性方式调节。此外，我们发现从暴露于缺氧的RMS细胞收获的条件培养基（CM）激活并刺激人脐静脉内皮细胞（HUVEC）的趋化反应，并且IL-8负责缺氧相关效应。最后，通过使用shRNA，人RH-30细胞中IL-8的表达下调。我们注意到，如果将这种RMS细胞注射到免疫缺陷小鼠的骨骼肌中，则其肿瘤形成能力降低。我们得出结论，IL-8是人RMS细胞在缺氧条件下释放的关键促血管生成因子，靶向IL-8可能被证明是抑制RMS生长的一种新的有效策略。
Rhabdomyosarcoma (RMS) is the most common soft‐tissue sarcoma of adolescence and childhood. Because RMS tumors are highly vascularized, we sought to determine which factors secreted by RMS cells are crucial in stimulating angiogenesis in response to hypoxia. To address this issue, we evaluated expression of several proangiogenic factors [interleukin (IL)‐8, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)‐2, stromal‐derived factor (SDF)‐1, hepatocyte growth factor (HGF) and leukemia inhibitory factor (LIF)] in 8 human RMS cell lines in both normal steady‐state and hypoxic conditions. We found by real‐time quantitative polymerase chain reaction (RQ‐PCR) and confirmed by enzyme‐linked immunosorbent assay (ELISA) that from all the factors evaluated, IL‐8, whose expression is very low in normoxia, had been very highly expressed and secreted by RMS cells lines during hypoxic conditions (∼40–170 times). Interestingly, this upregulation was not affected by knocking down hypoxia‐inducible factor (HIF)‐1α, but was inhibited by mitogen‐activated protein kinase (MAPK)p42/44 and phosphatidylinositaol 3‐kinase (PI3K)/AKT pathway inhibitors. This suggests that IL‐8 expression is regulated in an activating protein (AP)‐1‐ and nuclear factor (NF)‐κB‐dependent manner. Furthermore, we found that conditioned media (CM) harvested from RMS cells exposed to hypoxia activated and stimulated chemotactic responses in human umbilical vein endothelial cells (HUVECs) and that IL‐8 was responsible for hypoxia‐related effects. Finally, by employing shRNA, the expression of IL‐8 in human RH‐30 cells was downregulated. We noticed that such RMS cells, if injected into skeletal muscles of immunodeficient mice, have a reduced ability for tumor formation. We conclude that IL‐8 is a pivotal proangiogenic factor released by human RMS cells in hypoxic conditions and that the targeting of IL‐8 may prove to be a novel and efficient strategy for inhibiting RMS growth.