Merlin/FoxM1信号轴在PanIN恶性转化中的作用及机制

The key signaling pathways for Pancreatic Cancer (PC) progression are poorly understood, particularly transition from premalignant PanIN to invasive lesions. The studies on switch from PanIN to invasive PC are clinically relevant and significant, given the fact that PanIN are common in individuals who are older than 40 years. Our preliminary data suggest that drastic overexpression of FoxM1 in invasive PC as compared with that in PanIN, and genetic deletion of FoxM1 suppressed the formation of invasive PC from PanIN. Recently we found that there is a clear loss of Merlin expression in PC, and the reduction or loss of Merlin expression would alter the expression of FoxM1. Under previous studies, we have designed 3 specific aims to determine what genetic and epigenetic mechanisms underlying the reduced or lost expression of Merlin in PC, to determine whether and how Merlin regulate the expression and function of FoxM1, to determine the critical role and mechanism of Merlin/FoxM1 during transition from PanIN to invasive PC, furthermore, these results will be validated in transgenic animal model. Better understanding the key molecular event during the malignant transformation of PanIN, especially the function and mechanism of Merlin/FoxM1, would provide novel, effective clues for the intervention, diagnosis and therapy for the early stage of Pancreatic Cancer.

胰腺癌发生发展过程中的关键信号通路，尤其是PanIN（胰腺导管内瘤变）向胰腺癌转化的具体机制尚不清楚，而PanIN特别是低级别病变在40岁以上中老年人群中普遍存在。因此，探索PanIN恶性转化的具体机制尤为重要。前期研究提示FoxM1在PanIN向胰腺癌转化的过程中表达差异显著，转基因动物模型证实敲除FoxM1的表达可延缓PanIN形成侵袭性胰腺癌；随后研究发现抑癌基因Merlin在胰腺癌低表达，且可调控FoxM1的表达。本课题拟深入分析Merlin在胰腺癌低表达或者缺失表达的遗传学及表观遗传学机制，明确Merlin调控FoxM1表达的具体机制，通过转基因动物模型分析验证Merlin/FoxM1信号轴在PanIN恶性转化以及胰腺癌发生发展的作用。以期加深对Merlin抑癌功能的认知，发现潜在的预测PanIN恶性转化的分子标志事件，为胰腺癌早期病变的预防及诊治提供新思路。

胰腺癌是恶性程度最高的肿瘤之一，其发病隐匿，病程进展迅速，且缺乏有效的治疗手段，预后极差。而胰腺癌发生发展过程中的具体分子机制尚不清楚。既往研究提示FoxM1在PanIN向胰腺癌恶性转化的过程中表达差异显著，转基因动物模型证实敲除FoxM1的表达可延缓PanIN形成侵袭性胰腺癌；随后研究发现抑癌基因Merlin在胰腺癌低表达，且可调控FoxM1的表达。本课题在既往研究基础上深入分析Merlin在胰腺癌低表达或者缺失表达的遗传学及表观遗传学机制，明确Merlin调控FoxM1表达的具体机制，通过模式动物阐明Merlin/FoxM1信号轴在胰腺癌发生发展的作用。以期加深对Merlin抑癌功能的认知，为胰腺癌早期病变的预防及诊治提供新思路。. 本项目在既往研究以及预实验基础上，采用经典的分子生物学和模式动物等方法，主要获得以下研究结果：1）Merlin在人胰腺癌及胰腺癌细胞系中低表达，且与肿瘤T分期、淋巴结转移以及肿瘤分化呈负相关；2）功能研究发现过表达Merlin可抑制胰腺癌细胞的体内外生长、侵袭及转移；3）Merlin可抑制Wnt/β-Catenin信号通路下游靶基因的表达，以及β-Catenin蛋白的核表达，而过表达FoxM1可减弱Merlin对Wnt/β-Catenin信号通路的抑制效应；4）进一步机制研究发现，Merlin可通过泛素化影响FoxM1蛋白的稳定性，进而抑制β-Catenin的核转位。. 本项目首次定义了Merlin-FoxM1信号轴，阐明Merlin通过泛素化作用影响FoxM1蛋白的稳定性，进而抑制β-Catenin的核转位，通过负性调控Wnt/β-Catenin信号通路抑制胰腺癌的进展。