非小细胞肺癌脑转移特异性调控分子miR-143的作用及机制

Brain metastasis is one of the main reason for the death of lung cancer. Therefore, the identification of novel therapeutically targets on the basis of the molecular mechanisms responsible for the metastasis of NSCLC is a major and important challenge for lung cancer treatment. Our recent study revealed that miR-143 were significantly up regulated (4.3 fold) in brain metastasis compared corresponding lung primary tumor obtained from 7 patients that matched the filter criteria by use of Exiqon mercury LNA microRNA array (human cancer, 84 genes). The positive rate of miR-143 in stage IV NSCLC patients with brain metastasis (31/40) was significantly (p<0.05) greater than that in patients without brain metastasis (12/40). Overexpression of miR-143 can trigger the migration and invasion of NSCLC cells and epithelial mesenchymal transition (EMT) and then increase the capability for acrossing blood brain barrier (BBB). Then we hypothesized that miR-143 can modulate the brain metastasis of NSCLC specifically. In the present study, we will focus on the roles of miR-143 on the effects of EMT and passing through BBB, which are the two key processes for NSCLC brain metastasis, evaluate its down and up streams molecular signals, and then investigate the feasibility to use miR-143 as a biomarker for NSCLC brain metastasis or as a target for clinical therapy. Our study will break our cognitive limitation that there is no drug target for NSCLC brain metastasis and afford new approach to treat NSCLC.

脑转移是肺癌患者主要死因之一。目前关于非小细胞肺癌（NSCLC）脑转移的治疗手段及机制认知均非常有限。我们用7例NSCLC患者肺原发灶及脑转移灶配对标本行miRNA芯片分析，发现miR-143在脑转移灶中表达量为肺原发灶的4.3倍，原位杂交实验显示其在IV期NSCLC脑转移阳性组（31/40）患者中表达率显著高于（p<0.01）脑转移阴性组（12/40），且其可显著促进NSCLC细胞上皮间质化（EMT）及穿透血脑屏障（BBB）的能力，从而提示miR-143可能介导NSCLC特异性脑转移过程。本研究拟集中探讨miR-143在肺癌脑转移过程两大关键步骤EMT及穿透BBB中的作用及分子机制，阐明其生成的上游调控信号，并系统评价其作为NSCLC脑转移预警分子标志物及治疗靶标的可行性。旨在为探索NSCLC脑转移机制提供新的研究思路和对象，并为临床NSCLC脑转移预测及治疗提供具有重大潜力的分子靶标。

背景：脑转移（BM）是肺癌患者死亡的主要原因之一，目前关于非小细胞肺癌（NSCLC）脑转移的治疗手段及机制认知均非常有限。.方法：对配对原发性肺癌和脑转移患者病理组织标本检测miRNA表达谱，研究了miR-143-3p对肺癌脑转移的影响及其相关机制。.结果：与原发肺癌组织相比，miR-143-3p在配对BM组织中上调并提高对体外血脑屏障（BBB）模型的侵袭力和血管形成能力， miR-143-3p可通过靶向血管抑制素-1（VASH1）的3‘UTR 的三个结合位点来抑制其表达。同样，VASH1可以增加VEGFA的泛素化介导蛋白酶体的降解，并可以使微管蛋白解聚去酪氨酸化，增强细胞的运动能力。此外，甲基转移酶Mettl3可增加前体miR-143-3p的剪接。此外，miR-143-3p/VASH1通路可能为肺癌体内进展和总体生存率的不良预后因素。.结论：我们的研究提示了miR-143-3p / VASH1通路在肺癌脑转移中的起因作用，并提示了它们在肺癌发病机理中的关键作用。