Galectin-3通过β-Catenin信号通路调控血管生成促进肝癌转移分子机制的初步研究

Angiogenesis is an essential step in tumor invasion and metastasis. Recent reports demonstrated that Galectin-3 plays a critical role in tumor metastasis. However, the role of Galectin-3 in modulating angiogenesis and metastasis in hepatocellular carcinoma (HCC) remains unknown. In a recent work we demonstrated that Galectin-3 expression in HCC tissues was significantly higher than that in the matched non-tumorous tissues, and Galectin-3 expression was positively correlated with angiogenesis. Furthermore, we found that Galectin-3 could promote tumor migration and invasion in vitro, and lung metastasis in vivo, which might be associated with β-Catenin pathway activation. Therefore, we hypothesized that Galectin-3 might facilitate angiogenesis and liver cancer metastasis via β-Catenin pathway. In this project, we examine the effect of Galectin-3 on angiogenesis and metastasis in HCC. We will identify the role of Galectin-3 in modulating tumor angiogenesis through activatingβ-Catenin pathway, and study the role of key secreted protein in tumor angiogenesis and metastasis, thus elucidating new mechanisms of how Galectin-3 promote angiogenesis and liver cancer metastasis and providing new clues for the treatment of HCC patients.

血管生成是肿瘤侵袭转移的重要一环，有研究证实Galectin-3在肿瘤转移中发挥重要作用，但与肝癌血管生成和转移的机制尚不明确。我们前期研究发现Galectin-3在肝癌组织中的表达显著高于癌旁，且与肿瘤血管生成呈正相关；细胞和动物模型等证实Galectin-3具有促进肝癌细胞的迁移、侵袭以及转移致瘤的作用，该作用可能与Galectin-3对β-Catenin通路调控有关。但Galectin-3通过β-Catenin通路调控血管生成促进肝癌转移的具体机制尚不清楚。本项目拟探讨Galectin-3在肝癌中的表达与肿瘤血管生成和转移的关系及激活β-Catenin信号通路促进血管生成的机制，并在此基础上研究β-Catenin通路关键分泌蛋白对肝癌血管生成和转移的作用，以期阐明Galectin-3通过β-Catenin通路调控血管生成促进肝癌转移的新机制，为将来肝癌的临床治疗提供新的线索。

血管生成是肿瘤侵袭转移的重要一环，有研究证实Galectin-3在肿瘤转移中发挥重要作用，但与肝癌血管生成和转移的机制尚不明确。我们前期研究发现Galectin-3在肝癌组织中的表达显著高于癌旁，且与肿瘤血管生成呈正相关；细胞和动物模型等证实Galectin-3具有促进肝癌细胞的迁移、侵袭以及转移致瘤的作用，该作用可能与Galectin-3对β-Catenin通路调控有关。但Galectin-3通过β-Catenin通路调控血管生成促进肝癌转移的具体机制尚不清楚。通过本项目，我们证明：Galectin-3显示与血管侵犯和患者低生存率密切相关；Galectin-3显著参与了肝癌细胞的转移相关过程，如血管生成和上皮-间质转化(EMT)；机制上，Galectin-3激活PI3K-Akt-GSK-3β-β-catenin信号级联;β-catenin/TCF4转录复合物直接靶向IGFBP3和vimentin，分别调节血管生成和EMT；在动物模型中，Galectin-3通过β-catenin信号通路促进了肝癌细胞的肿瘤发生和转移；此外，Galectin-3-β-catenin信号通路的分子缺失可协同改善索拉非尼的抗肿瘤作用。本项目阐明了Galectin-3-β-catenin-IGFBP3/vimentin信号级联控制肝癌转移的中心机制，为预测血管转移和索拉非尼耐药提供了可能的生物标志物，同时也为肝癌患者治疗提供潜在治疗靶点。