外泌体-miR-301a在乏氧微环境中调控恶性胶质瘤血管生成拟态的机制研究及其对放疗敏感性的影响

Targeted therapy to vasculogenic mimicry could enhance radiosensitivity by preventing the ischemia and hypoxia of various tumors. In the previous study, we found that exo-miR-301a characteristically expressed and secreted by hypoxic malignant glioma cells, and is a potent regulator of vasculogenic mimicry. The potential mechanism is activating Wnt/β-catenin pathway by targeting TCEAL7. Based on the above results, we aim to explore the mechanism of exo-miR-301a modulates vasculogenic mimicry and involves in radiosensitivity of malignant glioma in hypoxia microenvironment. To solve the following problems: firstly, investigate the influence of hypoxia station and exo-miR-301a to vasculogenic mimicry in malignant glioma. Furthermore, validate the mechanism of exo-miR-301a in vasculogenic mimicry is regulating Wnt/β-catenin pathway by directly targeting TCEAL7. In addition, identify down-regulation of exo-miR-301a could significantly enhance radiation sensitivity of malignant glioma in vitro and vivo. Taken together, this subject research will supply therapeutic potential of radiotherapy and provide an importantly experimental groundwork for the development of new drugs in the treatment of malignant glioma.

抑制血管生成拟态的形成，能够增加肿瘤氧合状态，使之成为更有效的放疗分割照射靶点。我们前期研究发现，恶性胶质瘤在乏氧微环境中释放外泌体-miR-301a，影响血管生成拟态，其可能作用机制是通过靶向下调TCEAL7的表达，激活Wnt/β-catenin信号通路。基于此，本课题提出研究假说：降低乏氧微环境中外泌体-miR-301a的表达，通过调控Wnt/β-catenin信号通路抑制血管生成拟态，达到增加恶性胶质瘤放疗敏感性的目的。拟解决以下问题：乏氧和外泌体-miR-301a在恶性胶质瘤血管生成拟态形成中的作用；外泌体-miR-301a参与恶性胶质瘤血管生成拟态的分子机制的研究；体内外实验证实外泌体-miR-301a通过Wnt/β-catenin信号通路，促进血管生成拟态形成，影响恶性胶质瘤放疗敏感性。本项目将当前研究的前沿领域紧密结合，以期为恶性胶质瘤的放疗增敏研究提供重要的理论基础。

Exo-miRNA转运在调节肿瘤的发展和转移中有重要作用，并可作为miRNA靶向治疗的新研究方向。抑制血管生成拟态的形成，能够增加肿瘤氧合状态，使之成为更有效的放疗分割照射靶点。在本项目研究中，我们证实恶性胶质瘤在乏氧微环境中释放外泌体-miR-301a，影响血管生成拟态，其作用机制是通过靶向下调TCEAL7的表达，激活Wnt/β-catenin信号通路。进一步研究证实，TCEAL7在恶性胶质瘤中发挥抑癌基因的作用；TCEAL7负调控Wnt/β-catenin信号通路；降低乏氧微环境中外泌体-miR-301a的表达，TCEAL7表达升高，通过调控Wnt/β-catenin信号通路抑制血管生成拟态，达到增加恶性胶质瘤放疗敏感性的目的。体内实验证实外泌体-miR-301a通过Wnt/β-catenin信号通路，促进血管生成拟态形成，影响恶性胶质瘤放疗敏感性。本项目揭示恶性胶质瘤Exo-miR-301a与肿瘤微环境之间的异常调节和VM的分子调节通路，为达到针对肿瘤细胞的可塑性和内环境治疗肿瘤的目的提供了可靠的理论依据。