Sox11 prevents tumorigenesis of glioma-initiating cells by inducing neuronal differentiation.
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.
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Takuichiro
T
Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Japan.
Takezaki
Tatsuya
T
Nakatani
Yuka
Y
Nakamura
Hideo
H
Kuratsu
Jun-ichi
J
Kondo
Toru
T
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018797:Cell Cycle Proteins / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055751:SOXC Transcription Factors / Q000502:physiology*; D015996:Survival Rate; D014157:Transcription Factors / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C498423:Plagl1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C097473:SOX11 protein, human; D055751:SOXC Transcription Factors; C490793:Sox11 protein, mouse; D014157:Transcription Factors; D008156:Luciferases