RRC ID 81313
Author Ozaki S, Umakoshi A, Yano H, Ohsumi S, Sumida Y, Hayase E, Usa E, Islam A, Choudhury ME, Nishi Y, Yamashita D, Ohtsuka Y, Nishikawa M, Inoue A, Suehiro S, Kuwabara J, Watanabe H, Takada Y, Watanabe Y, Nakano I, Kunieda T, Tanaka J.
Title Chloride intracellular channel protein 2 is secreted and inhibits MMP14 activity, while preventing tumor cell invasion and metastasis.
Journal Neoplasia
Abstract The abilities to invade surrounding tissues and metastasize to distant organs are the most outstanding features that distinguish malignant from benign tumors. However, the mechanisms preventing the invasion and metastasis of benign tumor cells remain unclear. By using our own rat distant metastasis model, gene expression of cells in primary tumors was compared with that in metastasized tumors. Among many distinct gene expressions, we have focused on chloride intracellular channel protein 2 (CLIC2), an ion channel protein of as-yet unknown function, which was predominantly expressed in the primary tumors. We created CLIC2 overexpressing rat glioma cell line and utilized benign human meningioma cells with naturally high CLIC2 expression. CLIC2 was expressed at higher levels in benign human brain tumors than in their malignant counterparts. Moreover, its high expression was associated with prolonged survival in the rat metastasis and brain tumor models as well as with progression-free survival in patients with brain tumors. CLIC2 was also correlated with the decreased blood vessel permeability likely by increased contents of cell adhesion molecules. We found that CLIC2 was secreted extracellularly, and bound to matrix metalloproteinase (MMP) 14. Furthermore, CLIC2 prevented the localization of MMP14 in the plasma membrane, and inhibited its enzymatic activity. Indeed, overexpressing CLIC2 and recombinant CLIC2 protein effectively suppressed malignant cell invasion, whereas CLIC2 knockdown reversed these effects. Thus, CLIC2 suppress invasion and metastasis of benign tumors at least partly by inhibiting MMP14 activity.
Volume 23(8)
Pages 754-765
Published 2021-8-1
DOI 10.1016/j.neo.2021.06.001
PII S1476-5586(21)00043-9
PMID 34229297
PMC PMC8260957
MeSH Animals Brain Neoplasms / diagnostic imaging Brain Neoplasms / etiology Brain Neoplasms / metabolism* Brain Neoplasms / pathology* Capillary Permeability / genetics Cell Line, Tumor Cell Movement Chloride Channels / genetics Chloride Channels / metabolism* Enzyme Activation Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Silencing Humans Immunohistochemistry Matrix Metalloproteinase 14 / genetics Matrix Metalloproteinase 14 / metabolism* Neoplasm Grading Neoplasm Invasiveness Neoplasm Metastasis Neoplasm Staging Prognosis Protein Binding Rats Tumor Microenvironment
Resource
DNA material pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)