Snail/TELB/PAI-1通路在鼻咽癌转移中的作用及临床意义

Distant metastasis is the main cause of treatment failure in nasopharyngeal carcinoma (NPC), with underlying molecular mechanisms remains undetermined. We applied home-made transcription factor gene chips to screen the high- versus low-metastasis NPC cells as well as the primary NPC versus lymph node metastasis from NPC. TELB was one of the transcription factors that were significantly highly expressed in the low-metastasis cells or primary NPC tissues. Further bioinformatics analyses showed that plasminogen activator inhibitor- 1(PAI-1) was one of the down-stream target genes of TELB. In NPC cells, the expression levels of TELB and PAI-1 has an inverse relationship with elevated TELB expression correlating with reduced PAI-1 expression and less abilities on migration and invasion. Further explorations showed that Snail, one of the key molecules regulating tumor metastasis, could negatively regulate the expression of TELB, therefore enhanced the metastasis in NPC cell lines, indicating that Snail may promote NPC metastasis through down-regulation of TELB. In this project by using applying cellular and molecular biology experiments, animal model, clinic samples with long term follow-up data, we will prove for the first time that TELB inhibits the metastasis of NPC through down-regulating PAI-1, and it is negatively controled by Snail. The goal of this proposed study is to further indentify the molecular mechanisms and clinical significance of Snail/TELB/PAI-1 pathway in NPC metastasis and provide a new target for prediction and treatment of NPC distant metastasis.

远处转移是鼻咽癌治疗失败的主要原因，但其分子机制未明。我们应用自制的转录因子基因芯片，分别在具有高/低转移潜能的鼻咽癌细胞系和人鼻咽癌原发灶/颈淋巴结转移灶配对样本中，筛选出转录因子TELB,具有潜在抑制鼻咽癌转移的功能。进一步的全基因组芯片及生物信息学分析显示： TELB的下游靶基因可能是纤溶酶原激活物抑制物1(PAI-1)，PAI-1启动子具有TELB的结合位点，且两者的表达水平在鼻咽癌细胞系中呈负相关，与细胞的迁移和侵袭能力相关。进一步的探索显示：转移相关的关键分子Snail能够负调控TELB。本项目拟在细胞水平和动物模型中，并用鼻咽癌组织标本明确Snail/TELB/PAI-1通路的分子机制和临床意义，将首次鉴定 转录因子TELB受Snail负调控，并通过进一步负调控PAI-1来调控鼻咽癌转移，可为鼻咽癌转移的分子机制研究提供新的思路，为防治鼻咽癌的远处转移提供新的靶点。

转移是导致鼻咽癌患者治疗失败的主要原因。然而，人们对鼻咽癌转移的分子机制了解甚少。本项目首次应用自己制备的包含所有人类转录因子和上皮间质转化标记的基因芯片，发现TEL2在鼻咽癌高转移细胞株与淋巴结转移组织中表达下调。TEL2能够直接抑制鼻咽癌细胞在体外的迁移、侵袭和体内转移，抑制鼻咽癌SERPINE1启动子。在鼻咽癌的临床样本中，我们发现TEL2 和 SERPINE1的表达呈负相关。TEL2 低表达和 SERPINE1高表达是鼻咽癌的不良预后因素，血清中的高浓度的SERPINE1也是不良预后因素，我们首次证明TEL2通过直接下调SERPINE1在鼻咽癌的转移中扮演重要角色，TEL2 / SERPINE1轴有可能发展为治疗转移鼻咽癌的新策略。