Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Department of Neurosurgery, Okayama City Hospital, Okayama, Japan.
Oncogene. 2018 Feb 8;37(6):777-786. doi: 10.1038/onc.2017.373. Epub 2017 Oct 23.
Glioblastoma has the poorest prognosis, and is characterized by excessive invasion and angiogenesis. To determine the invasive mechanisms, we previously used two glioma cell lines (J3T-1 and J3T-2) with different invasive phenotypes. The J3T-1 showed abundant angiogenesis and tumor cell invasion around neovasculature, while J3T-2 showed diffuse cell infiltration into surrounding healthy parenchyma. Microarray analyses were used to identify invasion-related genes in J3T-2 cells, and the expressed genes and their intracellular and intratumoral distribution patterns were evaluated in J3T-2 cell lines, human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens. To determine the role of the invasion-related genes, invasive activities were evaluated in vitro and in vivo. Fibroblast growth factor 13 (FGF13) was overexpressed in J3T-2 cells compared to J3T-1 cells, and in human glioma cell lines, human glioblastoma stem cells and human glioblastoma specimens, when compared to that of normal human astrocytes. Immunohistochemical staining and the RNA-seq (sequencing) data from the IVY Glioblastoma Atlas Project showed FGF13 expression in glioma cells in the invasive edges of tumor specimens. Also, the intracellular distribution was mainly in the cytoplasm of tumor cells and colocalized with tubulin. Overexpression of FGF13 stabilized tubulin dynamics in vitro and knockdown of FGF13 decreased glioma invasion both in vitro and in vivo and prolonged overall survival of several xenograft models. FGF13 was negatively regulated by hypoxic condition. Silencing of FGF13 also decreased in vivo bevacizumab-induced glioma invasion. In conclusion, FGF13 regulated glioma cell invasion and bevacizumab-induced glioma invasion, and could be a novel target for glioma treatment.
胶质母细胞瘤的预后最差，其特征是过度侵袭和血管生成。为了确定侵袭机制，我们之前使用了两种具有不同侵袭表型的神经胶质瘤细胞系（J3T-1 和 J3T-2）。J3T-1 表现出丰富的血管生成和肿瘤细胞围绕新生血管的侵袭，而 J3T-2 则表现出弥漫性细胞浸润周围健康实质。我们使用微阵列分析来鉴定 J3T-2 细胞中的侵袭相关基因，并评估这些表达基因及其在 J3T-2 细胞系、人神经胶质瘤细胞系、人神经胶质瘤干细胞和人神经胶质瘤标本中的细胞内和肿瘤内分布模式。为了确定侵袭相关基因的作用，我们在体外和体内评估了侵袭活性。与 J3T-1 细胞相比，FGF13 在 J3T-2 细胞中过表达，与正常人类星形胶质细胞相比，在人神经胶质瘤细胞系、人神经胶质瘤干细胞和人神经胶质瘤标本中也过表达。免疫组织化学染色和 IVY 胶质母细胞瘤图谱项目的 RNA-seq（测序）数据显示，FGF13 在肿瘤标本侵袭边缘的神经胶质瘤细胞中表达。此外，细胞内分布主要在肿瘤细胞的细胞质中，并与微管蛋白共定位。FGF13 的过表达稳定了体外微管蛋白动力学，而 FGF13 的敲低减少了体外和体内的神经胶质瘤侵袭，并延长了几种异种移植模型的总生存期。FGF13 受低氧条件的负调控。FGF13 的沉默也减少了体内贝伐单抗诱导的神经胶质瘤侵袭。总之，FGF13 调节神经胶质瘤细胞侵袭和贝伐单抗诱导的神经胶质瘤侵袭，可能成为神经胶质瘤治疗的新靶点。
