Clusterin与CD133相互作用在抗肿瘤治疗诱导胶质瘤干细胞扩增中的功能及机制

CD133 (also known as prominin 1), a transmembrane glycoprotein, is commonly used as a cell surface marker to isolate cancer stem cells (CSC) in several types of human tumors. CD133 plays critical roles in tumor initiation, invasion, migration and drug-fast. Thus, CD133 has been considered as a new target for cancer therapy. However, the ligand of CD133 remains elusive. Here, we found that CD133 physically interacted with Clusterin throurgh its extracellular domain. Clusterin promoted glioma stem cell self-renewal though CD133. Clusterin enhanced the interactin between CD133 and p85. It has been widely known that DNA damage promotes cells releasing Clusterin. Treatment with temozolomide indued Clusterin mRNA expression and promoted Clusterin releasing. The media form tumor cell treated with temozolomide promoted glioam stem cell proliferation. Thus, we speculate that DNA damage induced by chemotherapy effectively induces apoptosis and promotes cell releasing Clusterin. Clusterin paradoxically promotes neighbouring CSC repopulation through the interation with CD133. In this project, we intend to clarify the mechanism and fucntion of the interaction between CD133 and Clusterin using glioma stem cell model and glioma xenograft model. Furthermore,we perform to investigate the contribution of the interaction between CD133 and Clusterin in DNA damage induced by antitumor therapy promoting neighboring CSC repopulation. Through these efforts, firstly, we hope to illuminate clusterin-CD133-p85 signaling axis. Second, this project will uncover the mechanism of chemo-resistance in glioblastoma.

肿瘤干细胞标志物CD133在肿瘤启动、耐药、侵袭中发挥着重要的功能，有望成为肿瘤治疗的新靶点。但CD133如何感受外界环境仍然是“盲点”，并成为其在肿瘤干细胞功能研究和临床应用的瓶颈。我们前期研究发现: (1)CD133的胞外区和分泌型糖蛋白Clusterin相互作用;(2)Clusterin增强CD133与p85相互作用并通过CD133促进胶质干细胞自我更新;(3)化疗能够诱导肿瘤细胞分泌Clusterin，藉此促进胶质瘤干细胞自我更新。鉴于此，本项目拟利用人胶质瘤标本、胶质瘤干细胞模型和小鼠胶质瘤原位模型，阐释CD133和Clusterin相互作用机制、调控因素及其在化学治疗诱导胶质瘤干细胞扩增中的功能、机制，从而发现CD133的胞外相互作用分子，揭示出化学治疗诱导胶质瘤干细胞扩增的Clusterin-CD133-p85信号轴，为胶质瘤的治疗抵抗、开展胶质瘤干细胞的靶向治疗提供新思路。

肿瘤干细胞标志物CD133在肿瘤启动、耐药、侵袭中发挥着重要的功能，有望成为肿瘤治疗的新靶点。但CD133如何感受外界环境仍然是“盲点”，并成为其在肿瘤干细胞功能研究和临床应用的瓶颈。本项目利用人胶质瘤标本、胶质瘤干细胞模型、动物模型，阐释CD133和Clusterin相互作用机制、调控因素及其在化学治疗诱导胶质瘤干细胞增殖中的功能、机制。研究发现：化疗能够诱导肿瘤细胞分泌Clusterin，CD133的胞外区和分泌型糖蛋白Clusterin结合增强CD133与p85相互作用并通过CD133促进胶质干细胞自我更新；通过化合物芯片筛选发现LDN193189可以抑制CD133磷酸化、CD133与p85的结合，进而抑制CD133+肝癌干细胞的自我更新；CD133的848位赖氨酸泛素化修饰通过Tsg101依赖的途径促进CD133囊泡的释放并促进肿瘤细胞的迁移；CD133+肝癌干细胞表面的高甘露糖型N-糖链与淋巴管内皮细胞表面的高甘露糖受体结合促进肿瘤干细胞自我更新与免疫逃逸。研究成果发表Mol Cell Biol1篇、 Cancer letters1篇、FEBS letters1篇、 J hepatology1篇等4篇论文；申请1项专利。培养博士研究生3名。