ADAM17通过活化integrinβ1促进肝癌细胞运动模式转换及迁移侵袭的分子机制研究

Migration and invasion are crucial steps for hepatocellular carcinoma progression. Therefore, improved understanding of the molecular mechanisms of HCC invasion and metastasis is essential for the development of new therapeutic strategies. Our previous study has revealed that ADAM17（a disintegrin and metalloproteinase，ADAM） knockout in HCC cells effectively decreased the expression of active integrinβ1, and the migration and invasion potentials of HCC cells were also attenuated. However, the molecular mechanism for ADAM17 mediated regulation of integrin β1 remains unclear. Moreover, we want to further explore the role and mechanism of ADAM17- integrin β1 interaction in motility of HCC cells.. In this study, we will firstly confirm the role of ADAM 17 and integrin β1 in regulating migration and invasion of HCC cells via in vitro 3D model and in vivo invasion and metastasis assay. The mechanism underlying ADAM 17-integrin β1 mediated interconvertion of mobile modes, as well as migration and invasion will be explored. We will also try to find the potential of key molecules as targets for repressing the invasion and development of HCC.

肝癌细胞发生迁移侵袭是肝癌进展的重要环节。本项目前期预试验表明，敲除肝癌细胞中解聚素金属蛋白酶（a disintegrin and metalloproteinase，ADAM）17可以减弱整合素(integrin) β1的活性形式表达，并降低了肝癌细胞的迁移侵袭能力。然而，ADAM17对integrin β1活性调控的分子通路尚未阐明；ADAM17与integrin β1介导肝癌细胞运动的具体机制也有待探讨。. 本项目拟首先通过临床病理标本结合体外3D模型及体内侵袭转移试验，明确ADAM 17和integrin β1所形成的分子通路在肝癌细胞迁移侵袭中的作用；阐明ADAM 17-integrin β1通路通过直接或间接作用调控肝癌细胞运动模式，进而推动细胞迁移侵袭的分子机制，筛选参与肝癌细胞运动的关键分子，为探索肝癌转移新靶点、改善肝癌传统治疗效果提供一定的理论支持。

解聚素金属蛋白酶17(ADAM17)通过促进细胞增殖及迁移促进肿瘤发生发展。本课题研究了ADAM17及integrin通路激活对肝癌细胞恶性行为的影响。选取临床高通量的肝癌组织芯片及DEN诱导小鼠肝癌组织，对ADAM17及active integrin β1进行检测，发现二者呈现正相关。与癌旁组织相比，ADAM17及active integrin β1表达增强。Active integrin β1 表达与肿瘤大小及TNM分级相关。ADAM17及active integrin β1高表达预示着肝癌患者较差预后。ADAM17敲低及integrin β1拮抗抗体均减弱肝癌细胞迁移侵袭能力。ADAM17 过表达则呈现相反趋势。ADAM17低表达减弱肝癌细胞肝内生长及转移，并降低 active integrin β1, p-FAK, p-AKT, MMP-2 及 MMP-9表达。ADAM17低表达显著降低Notch1胞内段入核，而Notch1胞内段过表达使其重新入核并促进integrin β1活化。我们的结果证实，ADAM17-integrin β1 通路通过 integrin β1 下游分子网络及Notch1信号调节肝癌细胞迁移侵袭。将ADAM17作为靶标可能为肝癌转移抑制提供线索。