肺腺癌脑转移新机制：外泌体lncRNA SBF2-AS1调控miR-140/TFCP2轴介导血脑屏障损伤
批准号：
82103537
项目类别：
青年科学基金项目（C类）
资助金额：
30.0 万元
负责人：
张海涛
依托单位：
学科分类：
肿瘤复发与转移
结题年份：
2024
批准年份：
2021
项目状态：
已结题
项目参与者：
张海涛
关键词：
项目摘要
结项摘要
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中文摘要
肺腺癌脑转移发生率高、预后差，肿瘤外泌体介导血脑屏障损伤导致肿瘤脑转移已被证实但机制不清。研究表明肿瘤外泌体lncRNA SBF2-AS1促进肿瘤耐药发生，SBF2-AS1通过吸附miR-140调控下游基因，miR-140调节血管内皮细胞功能。我们前期实验发现肺腺癌脑转移患者肺癌组织及血清外泌体、A549细胞外泌体中SBF2-AS1含量升高；外泌体SBF2-AS1含量升高引起脑微血管内皮细胞内TFCP2表达上调、紧密连接蛋白ZO-1表达下调，且此效应分别被miR-140类似物、敲减TFCP2表达逆转；同时SBF2-AS1与TFCP2含有相同的miR-140竞争性结合序列。据此我们提出假设：肺癌外泌体SBF2-AS1调控miR-140/TFCP2轴介导血脑屏障损伤进而导致肺腺癌脑转移发生。本项目对阐明肺癌外泌体介导血脑屏障损伤导致肺癌脑转移的机制具有重要意义，为肺腺癌脑转移的防治提供新思路。
英文摘要
Brain metastasis of lung adenocarcinoma has a high incidence and poor prognosis. It has been confirmed that tumor exosomes mediate blood-brain barrier injury leading to tumor brain metastasis, but the mechanism is still unclear. Studies have shown that tumor derived exosomal lncRNA SBF2-AS1 promotes the occurrence of tumor drug resistance, SBF2-AS1 regulates downstream genes by adsorbing miR-140, and miR-140 regulates the function of vascular endothelial cells. Our previous experiment found that the content of SBF2-AS1 increased in exosomes of lung cancer tissues, serum in patients with brain metastasis of lung adenocarcinoma, and lung adenocarcinoma cell line A549. The increased content of SBF2-AS1 in exosomes caused the up regulation of TFCP2 expression and down regulation of tight junction protein ZO-1 expression in brain microvascular endothelial cells, and this effect should be reversed by miR-140 mimics and knockdown of TFCP2 expression, respectively. At the same time, we also found that SBF2-AS1 and TFCP2 share the same miR-140 competitive binding sequence. Therefore, we hypothesized that lung cancer exosomal SBF2-AS1 regulates the miR-140/TFCP2 axis in human brain microvascular endothelial cells and its downstream target genes mediate blood-brain barrier damage leading to brain metastasis of lung adenocarcinoma. This project is of great significance for elucidating the mechanism of lung cancer derived exosomes mediated blood-brain barrier injury leading to brain metastasis of lung cancer, and provides new ideas for the prevention and treatment of brain metastasis of lung adenocarcinoma.
近50%的肺腺癌患者在病程中均会出现肿瘤脑转移，但是目前针对肺癌脑转移的治疗效果极差。肺癌脑转移与其他器官靶向转移最关键的区别是肿瘤细胞需要穿越血-脑屏障。肿瘤外泌体介导血脑屏障损伤导致肿瘤脑转移已被证实但机制不清。通过生物信息学分析，我们发现Lnc-SBF2-AS1高表达的肺腺癌患者生存期显著降低。通过裸鼠肺癌脑转移模型证实Lnc-SBF2-AS1会增加肺癌脑转移的风险。利用体外细胞模型，Lnc-SBF2-AS1的过表达诱导肺癌细胞发生上皮-间质转化（EMT），从而增强其侵袭和迁移能力。此外，Lnc-SBF2-AS1通过肺癌来源的外泌体分泌到血液中，这些外泌体首先与血管内皮细胞相互作用，导致血管结构改变，增加转移风险。随后，它们通过血液循环运输，并被血脑屏障处的脑微血管内皮细胞摄取，导致血脑屏障功能障碍，进一步增加脑转移风险。脑微血管内皮细胞摄取外泌体Lnc-SBF2-AS1后，通过Lnc-SBF2-AS1/MiR-140/Slug 轴诱导内皮-间质转化（EndMT），导致血管内皮损伤和通透性增加。此外，也可通过Lnc-SBF2-AS1/MiR-143/PUMA轴降低紧密连接蛋白（Claudin-5、Occludin、ZO-1）的表达，导致细胞间隙增大，血管通透性增强，进而增加肺癌脑转移的风险。此项研究的发现进一步深入阐明了肺癌脑转移的机制，提示外泌体Lnc-SBF2-AS1可以作为肺癌脑转移的生物标志物和潜在的治疗靶点。
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