Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small-cell lung cancer cell survival in brain
Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small-cell lung cancer cell survival in brain
复制标题
脑微血管内皮细胞外泌体介导的S100A16上调赋予小细胞肺癌细胞在脑中的存活
DOI：
10.1096/fj.201800428r
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发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
Li, Bo
中科院分区：
文献类型：
--
作者：
Xu, Zhi-Hua;Miao, Zi-Wei;Li, Bo
小细胞肺癌（SCLC）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偏好。尽管在SCLC的新疗法方面做出了努力和进展，但伴有脑转移的SCLC患者的预后始终较差。因此，更好地了解SCLC脑转移的机制对于改善当前的治疗方法具有重要意义。在这项研究中，升高的S100 A16水平与SCLC脑转移相关，这是脑转移微环境引起的可能继发事件。利用体外细胞共培养系统，我们发现SCLC细胞与人脑微血管内皮细胞（HBMEC）共培养导致SCLC细胞中S100 A16的表达增加。相反，用GW 4869（一种外泌体释放抑制剂）处理HBMEC可显著阻断共培养SCLC细胞中的这种效应。或者，来自Western印迹分析和免疫荧光的结果表明，通过超离心纯化的HBMEC外泌体也诱导受体SCLC细胞中S100 A16从细胞质升高并易位到细胞核。抑制实验表明，升高的S100 A16有助于HBMEC外泌体在应激下对受体SCLC细胞的存活的益处。此外，Annexin V/propidium iodide和JC-1检测显示，S100 A16基因的表达可抑制SCLC细胞线粒体膜电位（m）的降低，增强细胞对应激条件下凋亡的抵抗力。进一步的结果表明，S100 A16介导的保护作用是由m中的一个重要元素--线粒体内膜中的蛋白质--抑制素（PHB）-1的存在引起的。相反，将PHB-I siRNA递送到S100 A16过表达的SCLC细胞中削弱了这些保护作用。我们的研究结果表明，升高的S100 A16通过调节线粒体功能在促进SCLC细胞的存活中起积极作用，将S100 A16鉴定为SCLC脑转移的重要潜在靶点。H、Miao，Z.- W.，Jiang，Q.- Z.，Gan，D.- X.，魏，X。- G.，薛，X。- Z.，李，J-问：Zheng，F.，秦，X。- X.，方，W.- G.，陈玉- H、李B。脑微血管内皮细胞外泌体介导的S100 A16上调赋予脑中小细胞肺癌细胞存活
Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for early brain metastases. Despite efforts and advances in new therapeutics for SCLC, the prognosis of patients with SCLC with brain metastases is consistently poor. Therefore, a better understanding of the mechanisms of SCLC brain metastasis is important in improving current treatments. In this study, elevated S100A16 levels were associated with SCLC brain metastases, which was a possible secondary event arising from the brain metastatic microenvironment. Using an in vitro cell coculture system, we found that the coculturing of SCLC cells with human brain microvascular endothelial cells (HBMECs) led to an increased expression of S100A16 in SCLC cells. Conversely, treatment of HBMECs with GW4869, an inhibitor of exosome release, significantly blocked this effect in the cocultured SCLC cells. Alternatively, the results from Western blot analyses and immunofluorescence indicated that the HBMEC exosomes purified by ultracentrifugation also induced the elevation and translocation from the cytoplasm to the nucleus of S100A16 in the recipient SCLC cells. The inhibition experiments demonstrated that elevated S100A16 contributed a benefit of HBMEC exosomes for the survival of the recipient SCLC cells under stress. Moreover, the elevation of S100A16 in SCLC cells prevented the loss of mitochondrial membrane potential (m) and enhanced resistance to apoptosis under stressful conditions, which were determined by Annexin V/propidium iodide and JC-1 assay. Further results showed that the S100A16-mediated protective effect was caused by the presence of an important element in m, prohibitin (PHB)-1, a protein in the mitochondrial inner membrane. Conversely, the delivery of PHB-1 siRNAs into S100A16 overexpressing SCLC cells weakened these protective effects. Our findings suggest that elevated S100A16 plays an active role in facilitating the survival of SCLC cells through modulating the mitochondrial function, identifying S100A16 as an important potential target in SCLC brain metastasis.Xu, Z.-H., Miao, Z.-W., Jiang, Q.-Z., Gan, D.-X., Wei, X.-G., Xue, X.-Z., Li, J.-Q., Zheng, F., Qin, X.-X., Fang, W.-G., Chen, Y.-H., Li. B. Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small cell lung cancer cell survival in brain.