ADAMTSL4调控赖氨酰氧化酶重塑ECM促进NSCLC脑转移的机制研究

非小细胞肺癌（NSCLC）脑转移发生率高、预后欠佳，然而其转移机制尚未完全阐明。细胞外基质（ECM）重塑在肿瘤细胞定植靶器官过程中发挥重要作用。申请者前期研究发现与亲本细胞相比，肺癌脑转移细胞系中ECM调控相关基因明显富集，其中分泌型调节蛋白ADAMTSL4在脑转移细胞系及脑转移灶中均显著上调，且该基因参与肺癌侵袭转移。新近研究表明，ADAMTSL4能够与赖氨酰氧化酶（LOX）结合，而LOX可催化ECM中IV型胶原蛋白交联，从而募集肿瘤细胞到达特定器官组织。据此我们首次提出ADAMTSL4通过调控LOX活性重塑ECM促进了肺癌细胞在脑组织中的定植。本研究拟利用ADAMTSL4高/低表达细胞系和肺癌脑转移动物模型，研究ADAMTSL4沉积对脑组织定植的影响，并利用结合位点突变等方法，重点探讨ADAMTSL4调控LOX活性参与肺癌脑转移的分子机制，以期为肺癌脑转移的防治及靶向治疗提供理论依据。

The incidence of non-small cell lung cancer (NSCLC) brain metastasis was high and the prognosis was extremely poor. However, the molecular mechanism of NSCLC brain metastasis is currently unclear. Tumor metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as extracellular matrix (ECM). Our previous research showed that the ECM regulation-related genes were significantly enriched in brain metastatic cell lines compared with parental cells, of which ADAMTSL4, a regulatory protein, was significantly up-regulated in both brain metastatic cell lines and brain metastases. The recent study indicated that ADAMTSL4 and LOX can interact specifically with each other, moreover, the LOX can crosslink collagen IV in the basement membrane at premetastatic sites, which was essential for CD11b+ myeloid cell recruitment. Therefore, we propose that ADAMTSL4 promotes the colonization of lung cancer cells in brain by regulating the activity of LOX. In this project, the ADAMTSL4 high/low expression cell lines and NSCLC brain metastasis animal models would be employed to study the effects of ADAMTSL4 deposition on brain metastases. Moreover, the molecular mechanism of ADAMTSL4 on regulating LOX activity involved in NSCLC brain metastases would be explored. The study would provide theoretical basis for the prevention and treatment of brain metastases from lung cancer.