Scavenger Receptor A1 Prevents Metastasis of Non-Small Cell Lung Cancer via Suppression of Macrophage Serum Amyloid A1
Scavenger Receptor A1 Prevents Metastasis of Non-Small Cell Lung Cancer via Suppression of Macrophage Serum Amyloid A1
复制标题
清道夫受体 A1 通过抑制巨噬细胞血清淀粉样蛋白 A1 预防非小细胞肺癌转移
DOI：
10.1158/0008-5472.can-16-1569
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发表时间：
2017
期刊：
影响因子：
11.2
通讯作者：
Chen Qi
中科院分区：
文献类型：
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作者：
Zhang Yan;Wei Yongyue;Jiang Bin;Chen Lili;Bai Hui;Zhu Xudong;Li Xiaoyu;Zhang Hanwen;Yang Qing;Ma Junqing;Xu Yong;Ben Jingjing;Christiani David C.;Chen Qi
肿瘤细胞和肿瘤相关巨噬细胞（TAM）之间的相互作用机制尚未完全了解。主要表达于巨噬细胞的清道夫受体A1（SR-A1）与肺肿瘤的发生有关。在这项研究中，我们使用群体遗传学，转录组学和功能分析来揭示SR-A1如何参与肺癌及其预后。在哈佛肺癌研究队列中，研究了SR-A1遗传变异与晚期NSCLC患者生存率的可能相关性。SR-A1中的两个SNPs（rs 17484273，rs 1484751）与该队列的总生存率显著相关。来自癌症基因组图谱的数据显示肺肿瘤组织中SR-A1的显著下调。SR-A1与预后的关联在肺癌转移的背景下在动物模型中得到验证。来源于SR-A1基因缺陷小鼠的巨噬细胞在肺癌模型中表现出加速转移。另一方面，SR-A1缺陷小鼠中的肿瘤细胞接种、迁移和侵袭以及肺癌组织中的巨噬细胞积聚增强。SR-A1缺失可通过MAPK/IκB/NFκB信号通路上调巨噬细胞中的血清淀粉样蛋白A1（SAA 1）。SAA 1在体外和体内促进肿瘤细胞侵袭和巨噬细胞迁移，但这些作用可被抗SAA 1抗体阻断。总之，我们的研究结果显示SR-A1如何通过下调TAMs中SAA 1的产生来抑制肺癌转移。Cancer Res; 77（7）; 1586-98。©2017 AACR.
Mechanisms of cross-talk between tumor cells and tumor-associated macrophages (TAM), which drive metastasis, are not fully understood. Scavenger receptor A1 (SR-A1) expressed primarily in macrophages has been associated with lung tumorigenesis. In this study, we used population genetics, transcriptomics, and functional analyses to uncover how SR-A1 is involved in lung cancer and its prognosis. SR-A1 genetic variants were investigated for possible association with survival of advanced stage NSCLC patients in the Harvard Lung Cancer Study cohort. Two SNPs (rs17484273, rs1484751) in SR-A1 were associated significantly with poor overall survival in this cohort. Data from The Cancer Genome Atlas showed considerable downregulation of SR-A1 in lung tumor tissues. The association of SR-A1 with prognosis was validated in animal models in the context of lung cancer metastasis. Macrophages derived from mice genetically deficient for SR-A1 exhibited accelerated metastasis in a model of lung cancer. On the other hand, tumor cell seeding, migration, and invasion, as well as macrophage accumulation in lung cancer tissue, were enhanced in SR-A1–deficient mice. SR-A1 deletion upregulated serum amyloid A1 (SAA1) in macrophages via MAPK/IκB/NFκB signaling. SAA1 promoted tumor cell invasion and macrophage migrationin vitroandin vivo, but these effects were blocked by administration of an anti-SAA1 antibody. Overall, our findings show how SR-A1 suppresses lung cancer metastasis by downregulating SAA1 production in TAMs.Cancer Res; 77(7); 1586–98. ©2017 AACR.