靶向PLEKHA5抑制黑色素瘤脑转移的研究

黑色素瘤的循环肿瘤细胞到脑后需穿过血脑屏障（BBB）、形成微克隆并生长才能形成转移瘤；我们已报道PLEKHA5是介导黑色素瘤脑转移的关键分子，能促进脑转移灶的生长，但PLEKHA5在黑色素瘤穿过BBB和形成微克隆方面的作用及机制尚不清楚。我们基于前期数据提出科学假设：PLEKHA5可结合PDK1活化AKT通路，不仅促进PDCD4的降解以增加基质金属蛋白酶（MMPs）的表达来降解BBB的紧密连接，还促进CD271的表达以增强黑色素瘤干细胞的致瘤能力促进微克隆的形成，因此靶向PLEKHA5可有效治疗黑色素瘤的脑转移。本项目拟首先用动物脑转移模型和体外BBB模型等阐明PLEKHA5在黑色素瘤穿过BBB、促进微克隆形成中的功能；再在分子水平阐明PLEKHA5通过AKT调节PDCD4-MMPs、CD271的机制。本研究为联合使用PLEKHA5、AKT的靶向抑制剂治疗黑色素瘤脑转移奠定数据和理论基础。

The circulating melanoma cells have to transmigrate the blood brain barrier（BBB），colonize and outgrow in the brain to form brain metastases. We identified PLKEHA5 was a mediator of melanoma brain metastasis and promoted the growth of melanoma brain metastasis. But the positive role and molecular mechanism of PLEKHA5 in melanoma transmigrating the BBB and colonization in the brain is largely unknown. Based on our data generated, we hypothesize: knocking down PLEKHA5 can significantly inhibit melanoma brain metastasis. Because PLEKHA5 actives AKT by physically binding to PDK1, then breaking down BBB by accelerating PDCD4 degradation, subsequently increasing matrix metalloproteases (MMPs) expression to digest the tight junctions of BBB; PLEKHA5 also promotes melanoma colonization by increasing CD271 expression that stands for melanoma stem cell characterization and population. In this study，firstly we intracardially inject melanoma cells with inducible PLEKHA5 expression in mouse model and use BBB model in vitro to study function role of PLEKHA5 in melanoma transmigrating BBB and colonization. Then investigate the molecular mechanism of PLEKHA5 in regulating PDCD4/MMPs、CD271 expression. Our research is providing solid data and evidence for melanoma brain metastasis therapy by combing inhibitors targeting to PLEKHA5 and AKT.