The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cells.
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.
Park
Hyo-Jung
HJ
Cell Growth Regulation Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul, 136-713, Korea.
Kim
Jun-Kyum
JK
Jeon
Hye-Min
HM
Oh
Se-Yeong
SY
Kim
Sung-Hak
SH
Nam
Do-Hyun
DH
Kim
Hyunggee
H
D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001254:Astrocytoma / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D016543:Central Nervous System Neoplasms; D056741:Cyclin D / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis; D057093:Orphan Nuclear Receptors; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D056741:Cyclin D; D007381:Intermediate Filament Proteins; C577484:NES protein, human; C088601:NR2E1 protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear