ARRB调控Wnt/β-catenin信号通路诱导血管内皮细胞necroptosis在非小细胞肺癌外渗与转移中的作用及机制研究

So far, it is lack of effective method to control and block up the invasion and metastasis of lung cancer cells. It has been confirmed recently that the amyloid precursor protein (APP) combined with death receptor-6 (DR6) induces necroptosis of vascular endothelial cells (EC), which promotes tumor cell extravasation and metastasis. However, it remains unclear how these processes are regulated on a molecular level. Our previous studies have proved that ARRB is closely related to NSCLC metastasis and prognosis. Our preliminary studies showed that ARRB affects the tumor cell transference in NSCLC and is related to the Wnt/β-catenin signaling pathway. Other studies have suggested that the Wnt/β-catenin signaling pathway can regulate programmed necrosis and bears some latent relation to APP. Based on the above findings, we hypothesized that ARRB regulates APP expression in NSCLC cells through Wnt/β-catenin signaling pathway, consequently prevents necroptosis of EC from DR6 activation and further inhibits NSCLC cell extravasation and metastasis. A variety of experimental techniques such as proteomics methods, RNA interference, tumor model in nude mice etc. will be performed to clarify the mechanisms of the EC necroptosis inhibited by ARRB via Wnt/β-catenin signaling pathway in NSCLC metastasis, hoping to provide a new therapeutic target for inhibition of NSCLC metastasis.

目前缺乏抑制NSCLC转移的有效手段。近来证实肿瘤细胞表达淀粉样前体蛋白（APP）与死亡受体-6（DR6）相结合诱发血管内皮细胞（EC）启动程序性坏死（necroptosis）是肿瘤细胞外渗转移的关键环节，但其上游调控机制不明。我们前期研究证实ARRB与NSCLC转移及预后密切相关。预实验显示ARRB影响NSCLC细胞转移特性并与Wnt/β-catenin信号通路有关。结合有研究表明该信号通路可调控细胞程序性坏死并与APP存在关联，我们推测ARRB通过Wnt/β-catenin信号通路调控NSCLC细胞APP表达，进而阻止DR6诱发EC发生程序性坏死，抑制NSCLC细胞外渗转移。本研究拟采取蛋白质组学、RNA干扰、裸鼠肿瘤模型等多种实验方法，从分子、细胞和动物水平阐明ARRB对Wnt信号通路的调控作用及其对EC程序性坏死和NSCLC肿瘤转移的影响及机制，为NSCLC转移的防治提供新靶点。

当前仍缺乏抑制非小细胞肺癌（NSCLC）转移的有效手段。肿瘤细胞表达淀粉样前体蛋白（APP）与死亡受体-6（DR6）相结合诱发血管内皮细胞（EC）启动程序性坏死（necroptosis）是肿瘤细胞外渗转移的关键环节，但其上游调控机制不明。本研究采用RNA干扰、裸鼠肿瘤模型等多种实验方法，从分子、细胞和动物水平阐明了ARRB对Wnt信号通路的调控作用及其对EC程序性坏死和NSCLC肿瘤转移的影响及机制，我们的研究证实ARRB与NSCLC转移及预后密切相关，ARRB影响NSCLC细胞转移特性并与Wnt/β-catenin信号通路有关，该信号通路可调控细胞程序性坏死并与APP存在关联，ARRB通过Wnt/β-catenin信号通路调控NSCLC细胞APP表达，进而阻止DR6诱发EC发生程序性坏死，抑制NSCLC细胞外渗转移，本研究预计转化后将为NSCLC转移的防治提供新的药物靶点。研究进行的三年中，本项目培养肿瘤学硕士研究生3名，协助培养肿瘤学博士研究生1名、硕士研究生1名。