Cathepsin L在调控电离辐射诱导的脑胶质瘤侵袭迁移中的作用

This study found that the expression of Cathepsin L active fragment was increased in human glioma cells after ionizing radiation, furthermore, Cathepsin L was shown to be present in the nucleus of certain cells postirradiation，and the transcription factor CTUL1, the downstream signaling of Cathepsin L, was also expressed at higher level in irradiated glioma cells. The role of cathepsin L was not only involved in EMT and the regulation of tumor microenvironment, but also participated in regulating cell motility via Rho protein family, moreover, the activation and nuclear translocation of cathepsin L postirradiation were closely related to p53 gene mutation in glioma cells. These data suggested that Cathepsin L could be the intersection of multiple signaling pathways involved in tumor invasion and migration. Based on the above results, this research focuses on the role for cathepsin L in migration and invasion induced by irradiation in glioma cells. Here, we undertake the comprehensive in vitro and in vivo studies by using cellular, molecular biology and animal experiment methods, as well as clinical glioma samples. This study will reveals the link between cathepsin L and the key molecules in regulating EMT in glioma cells, elucidate the mechanism of the correlation between the activation of cathepsin L and the gene mutation of P53 . Thus, Cathepsin L might be explored as a novel target for combined therapy and drug development of glioma.

本研究发现脑胶质瘤细胞在电离辐射（IR）作用下，组织蛋白酶L（Cathepsin L）活性片段表达增加，部分细胞发生核转位，其下游分子- - 转录因子CUTL1高表达，该作用不但涉及到上皮间质转化（EMT）过程，还参与肿瘤微环境调控，并且通过Rho家族蛋白调节肿瘤细胞的运动，更重要的是IR 诱导的Cathepsin L激活和核转位与胶质瘤细胞P53突变密切相关，提示Cathepsin L可能是肿瘤侵袭迁移过程中多条信号通路的一个交汇点。本课题旨在上述已有发现的基础上，从细胞、分子、裸鼠原位移植瘤模型并结合临床胶质瘤标本，进一步研究Cathepsin L在IR诱导的脑胶质瘤侵袭迁移中的生物学功能；揭示Cathepsin L在调控脑胶质瘤EMT过程中与关键责任分子的联系；阐明在IR作用下Cathepsin L的激活与P53突变之间的分子机制，为脑胶质瘤综合治疗及药物开发提供新靶点。

本研究发现脑胶质瘤细胞在电离辐射（IR）作用下，组织蛋白酶L（Cathepsin L）活性片段表达增加，部分细胞发生核转位，一方面将其下游分子--转录因子CUX1/p200加工成p110活性片段，该作用不但涉及到上皮间质转化（EMT）过程，还参与肿瘤微环境调控，另一方面，IR激活的Cathepsin L通过Rho家族蛋白调节肿瘤细胞的运动，并且促进GSK-3β 9位丝氨酸磷酸化，通过Akt/GSK3β/snail信号转导通路调控细胞侵袭迁移能力。更重要的是，实验证明P53突变的胶质瘤细胞在受到IR作用后的EMT进程与Cathepsin L表达水平呈正相关，提示Cathepsin L可能是肿瘤侵袭迁移过程中多条信号通路的一个交汇点。本课题旨在上述已有发现的基础上，从细胞、分子、裸鼠原位移植瘤模型并结合临床胶质瘤标本，进一步研究Cathepsin L在IR诱导的脑胶质瘤侵袭迁移中的生物学功能；揭示Cathepsin L在调控脑胶质瘤EMT过程中与关键责任分子的联系；阐明在IR作用下Cathepsin L的激活与P53突变之间的分子机制，为脑胶质瘤综合治疗及药物开发提供新靶点。