IL-6/YAP信号通路促进成釉细胞瘤侵袭生长的作用及机制研究

Ameloblastoma (AB) is the most frequently encountered benign odontogenic tumor in oral facial area, which is locally aggressive and has a high risk of recurrence. However, the molecular mechanisms underlying the pathogenesis of this aggressive benign tumor remain largely unknown. Epithelial-to-mesenchymal transition (EMT) is a fundamental process for tumor invasion and metastasis. Our preliminary data showed that one of the most important EMT inducers, IL-6, was abundantly expressed in AB, while several key EMT- and stemness-regulatory genes, including YAP, are expressed in the epithelial compartments of solid subtype of AB. Most recently, a study (Nature, 2015) has firstly reported that IL-6 promoted epithelial regeneration by activating YAP signaling pathway. Based on the findings above, we speculate that, by activating YAP, IL-6 induces EMT and cancer stem cell (CSC)-like cell formation in AB epithelial cells, and consequently promotes the invasive growth of AB. Therefore, our project aims to determine the expression profiles of EMT- and stemness-regulatory genes, and its inducers in AB; explore the potential role and mechanisms of IL-6/YAP axis in the regulation of EMT process and CSC-like cell formation in AB epithelial cells. The completion of the proposed project will not only improve our understanding of the cellular and molecular mechanisms underlying the progression of AB, but also has the potential for the development of novel therapeutic strategies for AB therapy by specifically targeting IL-6/YAP axis.

成釉细胞瘤（AB）是口腔颌面部最常见的牙源性上皮性良性肿瘤，虽为良性，但其具有高度的侵袭性和极高的复发率。目前，AB侵袭生长的机制尚不明确。上皮间充质转化（EMT）是肿瘤侵袭和转移的一个重要发生机制。申请人前期研究发现，实性型AB高表达IL-6，且AB中的上皮细胞表达YAP等EMT相关转录因子及干细胞干性调控基因。2015年，Taniguchi K等（Nature）首次报道，IL-6通过激活YAP促进上皮组织的再生。基于以上发现，我们推测，IL-6可能通过激活YAP促进AB上皮细胞的EMT及CSC-样细胞形成，从而促进AB的侵袭生长。要验证该假设，本项目拟观察EMT在不同亚型AB中的发生及检测相关诱导因子；探讨IL-6在AB上皮细胞EMT及成瘤中的作用机制及以YAP为核心的信号通路。该项目的顺利实施将为阐明AB侵袭生长的机制及寻找防治AB新靶点提供科学基础。

成釉细胞瘤（AB）是口腔颌面部最常见的牙源性上皮性肿瘤，具有高度的侵袭性和复发率，其可侵蚀颌骨体及邻近牙齿的牙根，导致面部畸形和牙根吸收等。目前，关于AB的病因及侵袭生长机制尚不清楚，上皮-间充质转化（EMT）是牙齿发育和肿瘤细胞侵袭转移的重要机制。课题组前期研究提示，炎症因子IL-6、IL-8及促血管形成因子在AB中高表达，且其可能通过EMT或诱导肿瘤干细胞样细胞（CSCs）形成对肿瘤细胞的侵袭转移具有重要的调控作用。本课题重点研究了IL-8介导下的EMT在AB侵袭生长中的作用及机制，探讨了牙根吸收的免疫学机制。主要结果：1 发现IL-8在AB的上皮岛和周围的间质细胞中高表达，其通过提高肿瘤上皮细胞中β-catenin向细胞核中的转位促进AB肿瘤上皮细胞发生EMT过程，从而增强肿瘤细胞侵袭的能力。2 AB的膨胀性生长可侵袭肿瘤周围的牙根，使其发生牙根吸收，在压力的刺激下，牙周膜细胞可诱导巨噬细胞产生NLRP3炎症小体，激活NLRP3/caspase-1/IL-1β信号通路并促进M1型巨噬细胞的极化，诱发牙根吸收的发生。3 来源于牙囊的上皮细胞可能是AB形成的起源。AB的间质细胞可诱导牙囊上皮细胞发生EMT并成瘤，间质细胞通过激活牙囊上皮细胞中的Stat3/YAP信号通路，刺激EMT转录相关因子Zeb1和Slug表达增加，从而诱导EMT的发生。研究结果为进一步阐明AB的发生发展及侵袭生长的机制及构建基于白细胞介素及EMT相关调控因子的AB的临床干预路径提供依据。