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PMID:19808959

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Citation

Hide, T, Takezaki, T, Nakatani, Y, Nakamura, H, Kuratsu, J and Kondo, T (2009) Sox11 prevents tumorigenesis of glioma-initiating cells by inducing neuronal differentiation. Cancer Res. 69:7953-9

Abstract

Recent findings have shown that malignant tumors contain cancer-initiating cells (CIC), which self-renew and are tumorigenic. However, CICs have not been characterized properly due to lack of specific markers. We recently established a mouse glioma cell line, NSCL61, by overexpressing an oncogenic HRas(L61) in p53-deficient neural stem cells. Using limiting dilution assays, we show that only 2 of 24 NSCL61 clones retained their tumorigenicity in vivo, although the others also expressed oncogenic HRas(L61) and could proliferate in culture. A comparison of the gene expression profiles of tumorigenic and nontumorigenic clones showed that the tumorigenic clones had lost Sox11 expression. We show that overexpression of sox11 prevented tumorigenesis of NSCL61s by inducing their neuronal differentiation accompanied with decreased levels of plagl1. We also show that overexpression of plagl1 abolished neuronal commitment of nontumorigenic cells and induced them to become tumorigenic. Moreover, we show that human glioma-initiating cells lost sox11 expression, and overexpression of sox11 prevented their tumorigenesis in vivo. Together with the clinical evidence showing that downregulation of sox11 mRNA correlates with a significant decrease in survival, these findings suggest that Sox11 prevents gliomagenesis by blocking the expression of oncogenic plagl1.

Links

PubMed Online version:10.1158/0008-5472.CAN-09-2006

Keywords

Animals; Blotting, Western; Brain Neoplasms/metabolism; Brain Neoplasms/pathology; Brain Neoplasms/prevention & control; Cell Cycle Proteins/physiology; Cell Differentiation; Cell Proliferation; Chromatin Immunoprecipitation; Colony-Forming Units Assay; Gene Expression Profiling; Genes, Tumor Suppressor/physiology; Glioblastoma/metabolism; Glioblastoma/pathology; Glioblastoma/prevention & control; Humans; Luciferases/metabolism; Mice; Mice, Nude; Neoplasm Recurrence, Local/metabolism; Neoplasm Recurrence, Local/pathology; Neoplasm Recurrence, Local/prevention & control; Neurons/cytology; Neurons/metabolism; Oligonucleotide Array Sequence Analysis; RNA, Messenger/genetics; RNA, Messenger/metabolism; RNA, Small Interfering/pharmacology; Reverse Transcriptase Polymerase Chain Reaction; SOXC Transcription Factors/physiology; Survival Rate; Transcription Factors/physiology; Transfection; Tumor Cells, Cultured; Tumor Markers, Biological/genetics; Tumor Markers, Biological/metabolism; Xenograft Model Antitumor Assays

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SOX11

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SOX11

enables

GO:0000987: cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:PLAG1

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PLAG1

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PLAG1

involved_in

GO:0060252: positive regulation of glial cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SOX11

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SOX11

enables

GO:0001158: enhancer sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:SOX11

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SOX11

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SOX11

involved_in

GO:0045666: positive regulation of neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SOX11

involved_in

GO:0060253: negative regulation of glial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX11

involved_in

GO:0060253: negative regulation of glial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX11

involved_in

GO:0045666: positive regulation of neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX11

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX11

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SOX11

enables

GO:0001158: enhancer sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SOX11

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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