纳米材料硫化钨（WS2-PEG）诱导ROS过度积累促进神经母细胞瘤自噬性死亡的研究

Neuroblastoma is a common peripheral nervous system malignancy in pediatrics，and the cure rate of high-risk neuroblastoma is still low. It’s found that inducing autophagic cell death in neuroblastoma has a significant role in improving the cure rate of neuroblastoma. In our early study, we found that the WS2-PEG nanomaterial could induce autophgaic cell death of neuroblastoma. When treated with WS2-PEG, a large number of autophagosomes were observed in the cells, and the expression of LC3 and Beclin1 were significantly changed. In addition, an over-accumulation of intracellular ROS was observed too. These results suggested WS2-PEG nanomaterials may induce autophgaic cell death of neuroblastoma by destructing the balance of oxidation reduction, and over accumulating ROS. This project aims to explore the effect of WS2-PEG in anti neuroblastoma, and further explore the molecular mechanism of WS2-PEG inducing autophgaic cell death of neuroblastoma by over-accumulation of ROS, so as to provide a scientific basis for clinical application of WS2-PEG in neuroblastoma comprehensive treatment.

神经母细胞瘤是小儿常见的外周神经系统恶性肿瘤，目前高危神经母细胞瘤的治愈率较低，研究发现诱导神经母细胞瘤自噬性死亡对提高神经母细胞瘤的治愈率有很大的作用。我们前期研究发现，纳米材料硫化钨能够诱导神经母细胞瘤细胞自噬性死亡，细胞内出现大量自噬泡，细胞呈自噬状态，自噬相关蛋白LC3及Beclin1表达量明显变化；此外细胞内ROS大量积累。结果提示WS2-PEG纳米材料可能通过干扰细胞内氧化还原平衡、诱导 ROS 水平积累从而造成神经母细胞瘤发生自噬性死亡。本项目旨在探究纳米材料WS2-PEG对神经母细胞瘤的抗肿瘤作用，并进一步探索纳米材料WS2-PEG通过诱导ROS积累促进神经母细胞瘤自噬性死亡的分子机制，为纳米材料WS2-PEG在神经母细胞瘤临床综合治疗中的应用提供科学依据。

神经母细胞瘤是小儿常见的外周神经系统恶性肿瘤，目前高危神经母细胞瘤的治愈率较低，研究发现诱导神经母细胞瘤自噬性死亡对提高神经母细胞瘤的治愈率有很大的作用。本研究发现WS2-PEG纳米材料能够诱导神经母细胞瘤细胞自噬性死亡，细胞表现为线粒体嵴断裂，出现自噬小体，LC3-Ⅱ/LC3-Ⅰ比值显著升高，Beclin1表达量上调。WS2-PEG能够使细胞内ROS显著积累，细胞内Akt、FOXO1A、mTOR及 p70S6K蛋白的磷酸化水平明显降低，过表达ROS的抑制因子TIGAR，能够有效的减轻Akt、FOXO1A、mTOR及 p70S6K蛋白磷酸化的抑制作用。结果表明WS2-PEG能够通过诱导ROS水平增加，抑制PI3K/Akt/mTOR信号通路，从而诱导神经母细胞瘤细胞自噬性死亡，细胞内出现大量自噬泡，细胞呈自噬状态。本研究为纳米材料WS2-PEG在神经母细胞瘤临床综合治疗中的应用提供科学依据。