和厚朴酚调控Trk/STAT信号通路和肿瘤微环境对肺癌脑转移的化学预防作用研究

脑转移是导致肺癌患者死亡的重要原因，难以治疗，因此对肺癌脑转移的化学预防研究日益受到重视。申请人前期研究首次证实和厚朴酚是有效的肺癌化学预防剂；利用新近建立的肺癌脑转移小鼠模型，进一步发现和厚朴酚可有效抑制肺癌细胞的脑转移，并显著下调肺癌转移的关键分子酪氨酸激酶受体Trk及其下游信号STAT1/3/5磷酸化水平。另外，近期研究表明，和厚朴酚能有效穿越血脑屏障，可通过调节小胶质细胞分泌细胞因子（IL-6和TNF-α）等作用调节大脑微环境，提示和厚朴酚可能对肺转移癌在脑组织中的定植有化学预防作用。本项目在前期工作基础上，利用自行建立的小鼠肺癌脑转移模型，从整体、细胞和分子水平系统研究和厚朴酚对肺癌早期侵袭转移和脑组织定植的化学预防作用以及Trk-STAT信号通路和肿瘤微环境对肺癌脑转移的调控机制。

Brain metastases are an increasingly important cause of mortality in lung cancer patients, and present a therapeutic challenge. The applicant’s previous work has identified honokiol as a potent chemopreventive agent for lung cancer. Our recent preliminary data found that honokiol could significantly inhibit lung cancer cell migration, meantime, down-regulate receptor tyrosine kinase Trk, a key regulator of lung cancer metastasis, together with its downstream effector STAT1/3/5. Interestingly, several recent reports showed that honokiol can effectively pass through blood-brain barrier (BBB) and regulate glial cell function such as cytokine secretion. We therefore hypothesize that honokiol may have the potential to inhibit lung cancer brain metastasis through regulating Trk-STAT pathway and brain microenviroment. By using a valuable, traceable mouse lung tumor brain metastasis model, we propose to investigate whether honokiol could be a potential candidate agent for prevention of lung cancer brain metastasis and possible mechanisms. The aims of the proposed study include: to test whether honokiol can prevent lung cancer brain metastasis; to investigate the involvement of Trk-STAT pathway and regulation of brain microenvironment as the mechanisms underlying brain metastasis of lung cancer.