CD146作为关键节点调控非可控性炎症恶性转化分子机制研究

It has been well recognized that there is a close relationship between chronic non-resolving inflammation and malignant transformation. However, the molecular mechanism of this process is not clear. In the past three years, we have been focusing on cancer-related inflammation, angiogenesis and metastasis. Our study provided important evidence that CD146, as a node molecule, links chronic non-resolving inflammation and malignant transformation. In this project, we will continue to explore the molecular mechanism of CD146 in chronic non-resolving inflammation and malignant transformation. We will identify CD146 regulated network to clarify the molecular mechanisms of CD146 in the activation of downstream signaling pathways as well as its regulatory mechanisms. We will identify novel receptor or ligand of CD146 to uncover the mechanism of malignant transformation and angiogenesis. We will also resolve the 3-D structures of CD146 to better understand the structural basis of ‘tumor-specific conformation’ of CD146. Our study will not only provide novel molecular mechanism of CD146 in the cancer-related inflammation and malignant transformation, but also provide a new strategy for targeted therapy of chronic inflammation and cancer.

慢性炎症与肿瘤恶性转化之间存在内在紧密联系，然而其分子机制并不清楚。申请者前三年工作从CD146在慢性炎症引发恶性转化入手，延伸至血管生成和肿瘤转移，大胆提出血管新生是系慢性炎症和癌症的纽带，CD146是炎症恶性转化的关键节点分子。本项目将延续CD146在炎-癌转化中的重要作用，着重探索CD146与恶性转化和血管生成之间的互动关系；通过鉴定炎-癌恶性转化网络中CD146调控的分子群，阐明CD146活化下游信号通路的分子机制及其表达调控方式；通过对CD146相关受体、配体的鉴定，揭示CD146调控恶性转化及血管新生的分子机制；结合CD146“肿瘤特异性构象”的结构解析，为CD146的作用机制提供结构生物学基础；为深入理解慢性炎症向癌症转化的过程提供新机制，为靶向治疗慢性炎症及肿瘤提供新策略。

非可控炎症的恶性转化是由炎症发生-增殖-血管生成-侵袭-转移等多个环节组成的。申请者在本重大研究计划的资助下，在前三年的工作基础上，2014年继续深入探索了CD146在炎-癌恶性转化中的重要作用，取得了一系列原创性研究成果。申请者首次提出炎-癌恶性转化的纽带是血管新生，血管内皮CD146是恶性转化的关键节点。本研究揭示了CD146介导急、慢性炎症发展以及血管生成和肿瘤侵袭转移中的网络调控机制，取得一系列原创性进展：（1）发现CD146是促进炎症恶性转化的关键节点：通过构建炎症性肠病及其向肠癌的恶性转化小鼠模型，发现内皮特异性敲除CD146及抗体AA98治疗明显抑制炎症相关的肿瘤发生，表明血管内皮CD146是炎症-癌症转化的关键节点；（2）揭示了CD146在血管生成中受微环境诱导的转录后水平调控机制及其介导恶性转化中的网络上游和下游信号转导的途径；阐明了以CD146为调控核心的信号复合体。（3）阐明了血管内皮CD146在炎癌网络调节恶性转化中处于核心节点位置，明确了CD146上游网络因子除了VEGF和Wnt5a之外的新配体Netrin-1，进而活化下游NF-kB、ERK、AKT等重要炎癌信号的分子机制。总之，本研究以炎癌恶性转化的分子机制为导向，深入探索了CD146在微环境网络中的调控机制，发现炎症因子、mircroRNA等作为网络的上游调控CD146表达的机理；阐明了CD146作为关键节点分子活化NF-kB等重要信号通路，并促进肿瘤血管新生的新机制，丰富了“非可控性炎症恶性转化的调控网络与关键节点”的内涵。