Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis
Brain microvascular endothelium induced-annexin A1 secretion contributes to small cell lung cancer brain metastasis
复制标题
脑微血管内皮诱导膜联蛋白A1分泌促进小细胞肺癌脑转移
DOI：
10.1016/j.biocel.2015.06.019
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发表时间：
2015-09-01
影响因子：
4
通讯作者：
Li, Bo
中科院分区：
文献类型：
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作者：
Liu, Yi;Liu, Yong-Shuo;Li, Bo
小细胞肺癌是肺癌中最具侵袭性的组织学亚型，具有早期脑转移的强烈倾向。然而，细胞和分子基础知之甚少。在这里，我们提供了证据，揭示膜联蛋白A1在小细胞肺癌脑转移中的作用。首先，小细胞肺癌患者血清膜联蛋白A1水平升高与脑转移相关。在NCI-H446细胞（一种小细胞肺癌细胞系）中，膜联蛋白A1的水平也在迁移到小鼠脑中时上调。更有趣的是，当与人脑微血管内皮细胞共培养时，NCI-H446细胞以时间依赖性的方式分泌annexin A1，这通过ELISA和western blot检测共培养的细胞上清液中的annexin A1来鉴定。进一步的结果显示，使用中和抗体阻断共培养的细胞上清液中的膜联蛋白A1显著抑制NCI-H446细胞与脑内皮的粘附及其跨内皮迁移。相反，添加Ac 2 -26，膜联蛋白A1模拟肽，增强了这些效果。此外，在NCI-H446细胞中敲低膜联蛋白A1阻止其体外跨内皮迁移和体内转移到小鼠脑。我们的数据表明，脑微血管微环境中的小细胞肺癌细胞可以表达更多的annexin A1并将其释放到外面，这有助于小细胞肺癌细胞获得进入脑的恶性性质。这些发现为小细胞肺癌脑转移的治疗提供了一个潜在的靶点。(C)2015爱思唯尔有限公司版权所有。
Small cell lung cancer is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing to brain early. However, the cellular and molecular basis is poorly known. Here, we provided evidence to reveal the role of annexin A1 in small cell lung cancer metastasis to brain. Firstly, the elevated annexin A1 serum levels in small cell lung cancer patients were associated with brain metastasis. The levels of annexin A1 were also upregulated in NCI-H446 cells, a small cell lung cancer cell line, upon migration into the mice brain. More interestingly, annexin A1 was secreted by NCI-H446 cells in a time-dependent manner when co-culturing with human brain microvascular endothelial cells, which was identified with the detections of annexin A1 in the co-cultured cellular supernatants by ELISA and western blot. Further results showed that blockage of annexin A1 in the co-cultured cellular supernatants using a neutralized antibody significantly inhibited NCI-H446 cells adhesion to brain endothelium and its transendothelial migration. Conversely, the addition of Ac2-26, an annexin A1 mimic peptide, enhanced these effects. Furthermore, knockdown of annexin A1 in NCI-H446 cells prevented its transendothelial migration in vitro and metastasis to mice brain in vivo. Our data showed that small cell lung cancer cell in brain microvasculature microenvironment could express much more annexin A1 and release it outside, which facilitated small cell lung cancer cell to gain malignant properties of entry into brain. These findings provided a potential target for the management of SCLC brain metastasis. (C) 2015 Elsevier Ltd. All rights reserved.