CD146调控肝炎恶性转化的网络研究

申请者前期发现CD146是炎-癌转化中的关键节点分子，其成果受到国际同行的关注。最新发现，髓样抑制细胞MDSC有CD146-和CD146+两种亚型。其中，CD146+MDSC具有两种不同的功能，即在肝炎模型中促进炎症发展，而在肝癌模型中抑制炎症进展。这一新发现将揭示CD146有可能作为MDSC的一个重要的功能标志分子，调控MDSC在炎症和肿瘤两种不同炎症微环境中的功能转化，而这正是本领域目前悬而未决的问题。本项目拟从肝炎-肝癌恶性转化角度出发，引入系统生物学内源性核心网络，重点探索 CD146+MDSC在炎癌转化中的表达规律；通过内源性网络模拟，建立CD146+ MDSC在炎癌转化中的分子网络；预测调控CD146+ MDSC功能转换的分子群；结合临床标本，验证分子群在调控CD146+ MDSC功能转换中的作用，为MDSC提供重要的功能标记分子，阐明其在炎癌微环境中调控的网络机制。

In the previous three years, we have elucidated the important role of CD146 in promoting the malignant transformation by regulating angiogenesis. The balance between immunosuppression and Immune effector contributes to the malignant transformation of nonresolving inflammation. MDSC plays a dual role in inflammation, by inhibiting chronic inflammation as well as promoting the malignant transformation of inflammation. Due to the lack of important phenotypic markers, the functional conversion of MDSC can not be clearly defined. Recently, we found that CD146 was expressed on MDSC, and might reflect the role of MDSC in inflammation and HCC. In this project, we will continue to explore the role of CD146 in inflammation-driven tumorigenesis. We will determine whether CD146 could be used as MDSC functional phenotypic marker, reflecting the distinct role of MDSC in hepatitis and HCC. Based on the established the endogenous molecular–cellular network of CD146+ MDSC, we will predict the candidate molecules in controlling the function conversion of CD146+ MDSC, including the crosstalk with immune cells, stromal cells and liver cells. Collectively, our study will provide a novel marker for functional switch of MDSC during HCC initiation. Our study will also provide a new treatment strategy for HCC.