细胞核内MET通过调控IL-8表达影响肝内胆管癌血管生成的机制研究

As a transmembrane receptor, MET is closely related to the tumorigenesis and metastasis of intrahepatic cholangiocarcinoma (ICC), but the role of nuclear MET(nMET) in the development and angiogenesis of ICC is not well understood. Our preliminary studies revealed that nMET expression in primary ICC tissues is associated with significantly worse survival and early tumor recurrence in postoperative ICC patients. A strong positive correlation was found between the levels of nMET and microvessel density in ICC tissues. We further found that MET in the nucleus of ICC cells is a 60 kd protein comprising the carboxyl terminal of MET receptor. Overexpression of nMET in ICC cells significantly promoted the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of ICC, and nMET’s promotion of ICC angiogenesis involves the selective promotion of IL-8 expression. Thus, from the molecular, cellular and animal models, we aim to verify the clinical and biological contexts of nMET, and the concrete mechanism of nMET in the regulation of IL-8 expression in ICC. Our investigation may uncover the potential therapeutic targets in ICC treatment.

作为跨细胞膜受体，MET与胆管癌发生、演进等关系密切，但是细胞核内的MET在胆管癌进展、血管生成过程中扮演何种角色仍不清楚。课题组前期研究证实，细胞核内MET在肝内胆管癌组织中与患者总生存期和术后复发时间呈负相关，而与血管密度呈正相关。以此为切入点我们发现，在肝内胆管癌细胞中，细胞核内MET是分子量为60kd，包含MET蛋白C端结构域的胞质分子片段；进一步研究发现，细胞核内MET能够调控肝内胆管癌的血管生成过程，而IL-8是实现这一调控作用的关键因子。本课题将从临床、分子、细胞生物学及模式动物水平阐明细胞核内MET通过调控IL-8表达影响肝内胆管癌血管生成的具体机制，为细胞核内MET在肝内胆管癌血管生成及进展过程中的重要功能及作用机制提供理论依据，为肝内胆管癌临床抗血管治疗提供新思路及新靶点。

作为跨细胞膜受体，MET与胆管癌发生、演进等关系密切，但是细胞核内的MET(nMET)在胆管癌进展、血管生成过程中扮演何种角色仍不清楚。本研究发现，在肝内胆管癌组织中，细胞核内MET是分子量为60kd，包含MET蛋白C端结构域的胞质分子片段，并且细胞核内MET与患者总生存期和术后复发时间呈负相关，而与血管密度呈正相关。nMET在体内、体外实验均显示能够通过上调IL-8表达促进肝内胆管癌的血管生成过程，进而促进肿瘤的进展。探究其中的机制发现：nMET能够上调TAK1表达，进而磷酸化IKKβ，促进NF-κB p65的核内表达，从而上调IL-8的生成分泌。综上，本研究阐释了nMET参与肝内胆管癌血管生成的新机制，为临床治疗提供了理论基础和潜在靶点。