Abstract
A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was observed in a number of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf(-/-) astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf(-/-) astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Animals
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Astrocytes / metabolism
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Astrocytes / pathology
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Astrocytoma / genetics
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism
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Brain Neoplasms / pathology*
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cell Movement / physiology
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / pathology*
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Central Nervous System Neoplasms
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Cyclin D / genetics
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Glioma / genetics
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Glioma / metabolism
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Glioma / pathology*
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Humans
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Intermediate Filament Proteins / genetics
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Mice
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Mice, Nude
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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Nerve Tissue Proteins / genetics
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Nestin
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Neural Stem Cells / metabolism
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Neural Stem Cells / pathology*
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Neurogenesis
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Orphan Nuclear Receptors
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Prognosis
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Cytoplasmic and Nuclear / physiology*
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Up-Regulation
Substances
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Cyclin D
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Intermediate Filament Proteins
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NES protein, human
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NR2E1 protein, human
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Nerve Tissue Proteins
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Nes protein, mouse
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Nestin
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear