ERK/PFKFB3调控的内皮细胞糖酵解在血管瘤发展中的作用及机制研究

Infantile hemangioma (IH) is the most common benign tumor of infancy, and the robust angiogenesis is considered to be the important pathological basis for its rapid development. Recent studies have demonstrated that the PFKFB3-mediated glycolysis could drive pathological angiogenesis, therefore contibuting to the progression of various diseases. Our preliminary data has revealed the significantly increased expression of PFKFB3 in the proliferative infantile hemangiomas, indicating the PFKFB3-mediated glycolysis might contribute to the development of IH. Moreover, we have found that the direct interaction between ERK and PFKFB3, which might be the important mechanism for the regulation of energy metabolism in endothelial cells. Thus, the present project is designed to further investigate: (1) the role of PFKFB3-driven glycolysis in the proliferation, migration and angiogenesis of hemangima derived endothelial cells; (2) the underlying mechanism by which ERK regulates PFKFB3 in endothelial cells and the influence on the energy metabolism; (3) the feasibility and validity of PFKFB3-targeting in treating IH of the mouse model. Our research may further unmask the cell energy metabolism features during the development of IH, and would be beneficial for developing novel therapeutic strategies against IH and other angiogenesis related diseases.

血管瘤是婴幼儿最常见的先天性良性肿瘤，活跃的血管生成是血管瘤发生发展的重要病理基础。近来有研究指出PFKFB3介导的内皮细胞糖酵解水平异常升高是导致病理性血管生成的重要因素。本项目前期预实验结果已初步证实，在增生期血管瘤内皮细胞中PFKFB3表达显著上调，提示PFKFB3介导的内皮细胞糖酵解可能参与血管瘤的发展。此外，预实验结果显示ERK可与PFKFB3直接结合，可能是调控内皮细胞能量代谢的重要机制。本项目旨在进一步研究：(1) PFKFB3介导的糖酵解在血管瘤内皮细胞活化及血管生成中的作用；(2) 内皮细胞中ERK调控PFKFB3的具体分子机制，及其对内皮细胞能量代谢的影响；(3) 靶向PFKFB3抑制内皮细胞糖酵解治疗血管瘤的可行性及有效性。本项目的成功实施将有助于理解血管瘤发病过程中的能量代谢变化，并为开拓血管瘤等血管生成相关疾病的新疗法提供理论依据。

本项目研究表明PFKFB3及其他糖酵解相关分子在婴幼儿血管瘤及头颈部鳞状细胞癌内的内皮细胞中均呈阳性表达。通过与正常内皮细胞比较，我们发现血管瘤内皮细胞糖酵解水平显著提升，PFKFB3表达增强，抑制PFKFB3可显著抑制其糖酵解水平。研究表明PFKFB3小分子抑制剂可显著抑制血管瘤内皮细胞的增殖、迁移及成管；同时，该抑制剂还可抑制血管瘤内皮细胞的多向分化。内皮细胞中PFKFB3的表达受到多种生长因子，如血管内皮生长因子、碱性成纤维生长因子及淋巴毒素等调控；机制研究表明ERK信号通路主要参与了PFKFB3在内皮细胞中的表达调控。通过构建血管瘤裸鼠模型，我们进一步验证靶向PFKFB3可有效抑制血管瘤的发生及发展。同时，通过建立头颈鳞癌裸鼠移植瘤模型，我们证实靶向PFKFB3可通过抑制肿瘤血管生成抑制恶性肿瘤的发展。本项目的研究内容首次阐明了糖酵解在血管瘤发生发展过程中的作用，同时揭示PFKFB3可能作为婴幼儿血管瘤及恶性肿瘤治疗的潜在靶点。