Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion
Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion
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DOI：
10.1038/onc.2017.373
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发表时间：
2018-02-08
期刊：
影响因子：
8
通讯作者：
Date, I.
中科院分区：
文献类型：
--
作者：
Otani, Y.;Ichikawa, T.;Date, I.
胶质母细胞瘤预后最差，其特征是过度侵袭和血管生成。为了确定侵袭机制，我们以前使用了两种具有不同侵袭表型的胶质瘤细胞系（J3 T-1和J3 T-2）。J3 T-1表现出丰富的血管生成和肿瘤细胞浸润周围的新生血管，而J3 T-2表现出弥漫性细胞浸润到周围的健康实质。应用基因芯片技术检测J3 T-2细胞中侵袭相关基因的表达，并对J3 T-2细胞系、人脑胶质瘤细胞系、人脑胶质母细胞瘤干细胞和人脑胶质母细胞瘤标本中侵袭相关基因的表达及其在细胞内和瘤内的分布进行分析。为了确定侵袭相关基因的作用，在体外和体内评估侵袭活性。与J3 T-1细胞相比，成纤维细胞生长因子13（FGF 13）在J3 T-2细胞中过表达，与正常人星形胶质细胞相比，在人胶质瘤细胞系、人胶质母细胞瘤干细胞和人胶质母细胞瘤标本中过表达。IVY胶质母细胞瘤Atlas项目的免疫组织化学染色和RNA-seq（测序）数据显示，在肿瘤标本的浸润边缘的胶质瘤细胞中有FGF 13表达。胞内分布主要在肿瘤细胞的胞浆中，并与微管蛋白共定位。FGF 13的过表达在体外稳定了微管蛋白动力学，而FGF 13的敲低在体外和体内均降低了胶质瘤侵袭，并延长了几种异种移植模型的总生存期。FGF 13受缺氧条件负调控。FGF 13的沉默也降低了体内贝伐珠单抗诱导的胶质瘤侵袭。结论：FGF 13调控胶质瘤细胞侵袭和贝伐珠单抗诱导的胶质瘤侵袭，可能成为胶质瘤治疗的新靶点。
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.