基于抑制肿瘤相关巨噬细胞M2型极化的PZ8抗肿瘤转移作用机制研究

项目名称： 基于抑制肿瘤相关巨噬细胞M2型极化的PZ8抗肿瘤转移作用机制研究

项目编号： No.81473226

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨波

作者单位： 浙江大学

项目金额： 100万元

中文摘要： 抑制肿瘤相关巨噬细胞（TAM）的M2型极化被认为是极具应用前景的抗肿瘤转移新策略，但M2型极化的分子调控机制尚不明确，相关小分子化合物的发现也尚处于起步阶段。我们前期研究发现，天然来源活性单体PZ8可高效抑制TAM的M2型极化，且具显著抗肿瘤转移作用，M2型极化负调控蛋白SOCS3及相关信号分子可能参与了这一过程。本课题将清除或外源性导入巨噬细胞，研究PZ8通过抑制M2型极化发挥抗肿瘤转移作用。阐明SOCS3/JAK2/STAT6信号轴在PZ8抑制M2型极化中的作用地位及其与PZ8抗肿瘤转移活性的相关性，揭示PZ8激活的Notch与AMPK翻译后水平调控SOCS3的全新机制。本课题的研究，将发现新的具有选择性抑制M2型极化作用的天然来源化合物，阐明调控M2型极化的新分子机制，确证通过小分子化合物干预M2型极化实现抗肿瘤转移的可行性，为设计新型抗肿瘤转移化合物提供潜在靶点和新思路。

中文关键词： 肿瘤转移；肿瘤相关巨噬细胞；M2型极化；天然化合物

英文摘要： Inhibition of the M2 polarization of tumor associated macrophages (TAMs) is considered to be a promising strategy for the prevention of cancer metastasis. However, the molecular mechanism involved in M2 polarization is far from being elucidated, and the development of small molecule compounds that can interfere the M2 polarization is still in its early stage. Our previous studies have found that PZ8, an active monomer compound from natural sources, significantly suppresses the M2 polarization of TAM, and effectively prevents the metastasis of Lewis lung cancer. SOCS3 (a negative regulater of the M2 polarization) and its related signaling pathways might play an important role in this process. By applying elimination or exogenous import macrophage cells, we will further confirm that the anti-metastasis effect of PZ8 is through the inhibition of M2 polarization. In addtion,we will also reveal the role of SOCS3/JAK2/STAT6 signaling axis in PZ8-inhibited M2 polarization and cancer metastasis, and elucidate the underlying mechanisms involved in Notch and AMPK mediated post-translation modification of SOCS3. Our study will not only discover a natural compound that can specifically inhibit the M2 polarization of TAM, but also enhance our understanding of the molecular mechanisms involved in M2 polarization. Moreover, our study will confirm the feasibility of anti-metastasis strategies targeting macrophage polarization by small molecule compounds, in the hope to provide potential therapeutic targets for anti-metastasis therapy.

英文关键词： cancer metastasis;tumor associated macrophage;M2 polarization;natural compound