乳腺癌外泌体介导lncRNA GS1-600G8.5重塑血脑屏障促进肿瘤脑转移的作用机制研究

Brain metastasis is one of the leading causes for breast cancer death. However, the relevant mechanism regarding how the cancer cells cross the blood-brain barrier (BBB) to the brain, is still unclear. At present, the role of exosomal lncRNA in brain metastasis has not been reported. In our previous study, a high-metastatic breast cancer cell line was successfully constructed. The exosomes derived from the high-metastatic breast cancer cell significantly promoted the breast cancer cells through the BBB. LncRNA sequencing showed that lncRNA GS1-600G8.5 was significantly higher in the exosomes of high metastatic cells compared to that of lower metastatic cells. Moreover, interference of lncRNA GS1-600G8.5 inhibited the above functions of exosomes. We speculate that breast cancer cells regulate BBB through exosomes transporting lncRNA GS1-600G8.5 and promotes brain metastasis. This study intends to further verify the effect of exosomes and lncRNA GS1-600G8.5 on BBB based on our previous studies. The biological function and molecular mechanism of exosomal lncRNA GS1-600G8.5 will be investigated by using cell, animal models and clinical samples. These results might lay a foundation for the development of new methods for the prevention and treatment of brain metastasis in breast cancer.

脑转移是乳腺癌致死主要原因之一，但其是如何穿过血脑屏障（BBB）进入脑内的，相关机制尚未清楚。目前，外泌体lncRNA在脑转移中的作用还未见报道。本课题组在前期研究中，成功构建了高脑转移的乳腺癌细胞系，该细胞的外泌体可破坏BBB系统并促进乳腺癌细胞穿过BBB。测序显示lncRNA GS1-600G8.5在高脑转移乳腺癌细胞外泌体中较低转移细胞外泌体中高表达，且干扰lncRNA GS1-600G8.5可抑制外泌体上述功能。我们推测乳腺癌细胞通过外泌体介导lncRNA GS1-600G8.5调控BBB，促进乳腺癌脑转移。本研究拟在前期研究基础上进一步通过体内外验证外泌体和GS1-600G8.5对BBB调控作用，并采用细胞、动物模型和临床样本深入探讨外泌体GS1-600G8.5及其相关调控网络在脑转移中的生物学功能，探索乳腺癌发生脑转移的分子机理，为研发乳腺癌脑转移预防和治疗的新方法奠定基础。

乳腺癌是全球女性最常见的恶性肿瘤，是仅次于肺癌的第二大癌症死亡原因。虽然乳腺癌的治疗取得了许多进展，但乳腺癌合并脑转移患者的预后一直很差。因此，了解乳腺癌相关脑转移的细胞和分子机制，对于探索新的治疗靶点以开发有效的治疗方案，具有重要的意义。本课题研究了以下内容：研究外泌体对乳腺癌脑转移的调控作用，筛选和鉴定参与外泌体脑转移调控的lncRNA，研究lncRNA GS1-600G8.5调控网络。初步取得以下进展：获取乳腺癌脑转移细胞株MDABR3，成功建立体外血脑屏障（BBB）模型，研究MDABR3外泌体对BBB结构影响，外泌体lncRNA GS1-600G8.5影响BBB系统的体内外功能学研究，发现lncRNA GS1-600G8.5可能参与MAPK、Wnt通路。癌细胞如何通过BBB是研究一个难点，首次探讨乳腺癌细胞分泌的外泌体通过转运lncRNA，阐明外泌体lncRNA调控BBB可能机理以及介导肿瘤脑转移作用及相关机制，为后续研究提供一定参考依据。