TY - JOUR
T1 - Fibroblast growth factor 13 regulates glioma cell invasion and is important for bevacizumab-induced glioma invasion
AU - Otani, Y.
AU - Ichikawa, Tomotsugu
AU - Kurozumi, Kazuhiko
AU - Inoue, S.
AU - Ishida, J.
AU - Oka, T.
AU - Shimizu, T.
AU - Tomita, Y.
AU - Hattori, Y.
AU - Uneda, A.
AU - Matsumoto, Y.
AU - Michiue, H.
AU - Date, I.
N1 - Funding Information:
This study was supported by grants-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology to TI (No. 22591611 and No. 25462261) and KK (No. 23592125 and No. 26462182). We thank Dr H Wakimoto at Massachusetts General Hospital for providing the human glioblastoma-derived cancer stem cell line.18,42 We thank M Arao and U Ukai in the Department of Neurological Surgery and A Ueda in the Department of Physiology for their technical assistance. The following medical students also contributed to our experiments: K Yamamoto and Y Inoue. The accession number for the gene expression data reported in this paper is GSE88740.
Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018/2/8
Y1 - 2018/2/8
N2 - 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.
AB - 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.
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U2 - 10.1038/onc.2017.373
DO - 10.1038/onc.2017.373
M3 - Article
C2 - 29059154
AN - SCOPUS:85041497955
SN - 0950-9232
VL - 37
SP - 777
EP - 786
JO - Oncogene
JF - Oncogene
IS - 6
ER -
