TBLR1诱导鼻咽癌转移的分子机制

The epithelial- mesenchymal transition (EMT) play an important role in the metastasis of nasopharyngeal cancer （NPC）. Previous studies have reported that activating PI3K/AKT pathway can induce the EMT ofNPC cell then promote its metastasis of. Recently we found that TBLR1 is over-expressed in NPC and over-expression of TBLR1 was significantly correlated with poor progonostic.TBLR1 can suppresses cisplatin sensitivity of NPC cells(Coresponding author Molecular cancer IF=5.397).Further study we found that TBLR1 can activate the PI3K/AKT pathway by up-regulating the the expression of VEGF-C and AKT, while the mechanism remains unkonwn. The purpose of this study is to find the molecular mechanism of how TBLR1 up-regulating PI3K/AKT pathway , promote the lymphangiogenesis and induce metastasis of NPC by a series of cytological, molecular biology and animal experiments.We will also verify the corelation between over-expression of TBLR1 and PI3K/AKT pathway in clinical samples to further explain the mechanism of metastasis of NPC induced by TBLR1. Taken together,the study will provide new target and new theoretical basis for early detection of NPC metastasis.

上皮细胞间质化(EMT)在鼻咽癌转移早期扮演重要的角色。相关研究发现通过激活PI3K/AKT通路可诱导鼻咽癌细胞的EMT，从而促进鼻咽癌的转移；近期我们的研究发现TBLR1在鼻咽癌中高表达且高表达的TBLR1与鼻咽癌患者的不良预后显著相关；TBLR1可降低鼻咽癌细胞对铂类化疗药物的敏感性（通讯作者 Molecular cancer IF=5.397）。预实验中我们又发现TBLR1可通过上调VEGF-C及AKT的表达，激活PI3K/AKT通路，然而其详细分子机制有待阐明。本项目采用细胞、分子生物学及动物实验探讨TBLR1上调VEGF-C激活PI3K/AKT信号通路，促进淋巴管形成的同时诱导鼻咽癌细胞发生EMT的详细分子机制；并从临床标本中验证TBLR1与PI3K/AKT通路的关系，深层次解析TBLR1促进鼻咽癌转移的分子机制，为早期预测鼻咽癌诊治转移提供新的靶点及新的理论依据。

鼻咽癌（NPC）是一种高发于我国华南地区的上皮源性恶性肿瘤。远处转移现已成为鼻咽癌治疗失败的主要原因之一。本研究旨在探讨TBLR1调控鼻咽癌远处转移的分子机制。本课题组发现鼻咽癌组织中TBLR1的表达水平与不良预后显著相关。同时，过表达TBLR1可提高鼻咽癌细胞的迁移、侵袭能力，反之，下调TBLR1表达水平可抑制鼻咽癌细胞迁移及侵袭。进一步分子机制研究结果表明，TBLR1可促进VEGF-C表达，进而激活PI3K/AKT信号通路，促进鼻咽癌细胞的侵袭及转移。本研究成果表明：TBLR1在调控鼻咽癌细胞侵袭、转移中发挥重要作用，为鼻咽癌的分子生物分型及转移患者的个体化治疗提供了的潜在的分子生物指标及靶点。