半乳凝素-3（Gal-3）是肝癌治疗的潜在靶点。本项目基于糖基识别结构域（CRD）对内源Gal-3功能的竞争性抑制，在其N端嫁接具有抗肿瘤活性的Kringle结构域（PK5），获得新型Gal-3拮抗剂PK5-CRD。前期实验证实，与单独的PK5和CRD相比，融合蛋白PK5-CRD具有更强的体外体内抗肝癌活性，并且PK5-CRD能够抑制血管生成，促进T细胞肿瘤浸润和免疫相关细胞因子的表达。据此，本项目推测“Gal-3新型拮抗剂PK5-CRD通过抑制肿瘤血管生成和改善肿瘤免疫微环境发挥抗肝癌功能”。.在此基础上，本项目拟通过进一步研究PK5-CRD对血管生成信号通路的调控、对免疫细胞肿瘤浸润和细胞因子表达的调控、对T细胞体外杀伤功能及细胞因子分泌能力的调控，阐明PK5-CRD的抗肝癌机制。本项目的开展将为Gal-3的拮抗剂研究提供新思路，为靶向Gal-3的肝癌治疗和药物开发提供实验和理论依据。

Galectin-3 (Gal-3) has been demonstrated to be involved in the occurrence and development for liver cancer. And it has also been considered as one of the potential therapeutic targets for liver cancer. In order to generate the novel antagonist of Gal-3, PK5 (Plasminogen Kringle 5, an inhibitor of angiogenesis) was fused to the N-terminal of CRD (Carbohydrate-Recognition Domain, a competitive inhibitor of endogenous Gal-3), which was named PK5-CRD. Our previous studies demonstrated that PK5-CRD fusion protein exhibited stronger anti-tumor activity for liver cancer compared to PK5 and CRD both in vitro and in vivo. Moreover, PK5-CRD could also present anti-angiogenesis and enhance the infiltration of CD4+ as well as CD8+ T cell and expression of cytokines in liver cancer. Taken together, we hypothesize that PK5-CRD (a novel antagonist of Gal-3) could exhibit anti-tumor activity for liver cancer via inhibiting angiogenesis and modulating tumor immune microenvironment..To evaluate our hypothesis, the following studies will be performed: determining the regulation of PK5-CRD to angiogenesis signaling pathway, characterizing the modulation of PK5-CRD to tumor-infiltrating lymphocytes and expression of inflammatory cytokines, and analyzing the regulation of PK5-CRD to the function of cytotoxic T cell as well as cytokines production. Our results will provide a novel strategy for exploring antagonist of Gal-3, which might have major implications in the field of clinical treatment and drug development to liver cancer patient.