Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells

Wen-Shin Song; Yi-Ping Yang; Chi-Shuan Huang; Kai-Hsi Lu; Wei-Hsiu Liu; Wai-Wah Wu; Yi-Yen Lee; Wen-Liang Lo; Shou-Dong Lee; Yi-Wei Chen; Pin-I Huang; Ming-Teh Chen

doi:10.1016/j.jcma.2016.03.010

Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells

J Chin Med Assoc. 2016 Oct;79(10):538-45. doi: 10.1016/j.jcma.2016.03.010. Epub 2016 Aug 13.

Authors

Wen-Shin Song¹, Yi-Ping Yang², Chi-Shuan Huang³, Kai-Hsi Lu⁴, Wei-Hsiu Liu⁵, Wai-Wah Wu⁶, Yi-Yen Lee⁷, Wen-Liang Lo⁸, Shou-Dong Lee⁶, Yi-Wei Chen⁹, Pin-I Huang⁹, Ming-Teh Chen¹⁰

Affiliations

¹ Division of Neurosurgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
² Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, ROC.
³ Division of Colorectal Surgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
⁴ Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
⁵ Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, ROC.
⁶ Division of Gastroenterology, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
⁷ School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
⁸ School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
⁹ Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
¹⁰ School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei, Taiwan, ROC. Electronic address: mtchen@vghtpe.gov.tw.

PMID: 27530866
DOI: 10.1016/j.jcma.2016.03.010

Abstract

Background: Glioblastoma multiforme (GBM) is the most lethal type of adult brain cancer and performs outrageous growth and resistance regardless of adjuvant chemotherapies, eventually contributing to tumor recurrence and poor outcomes. Considering the common heterogeneity of cancer cells, the imbalanced regulatory mechanism could be switched on/off and contribute to drug resistance. Moreover, the subpopulation of GBM cells was recently discovered to share similar phenotypes with neural stem cells. These cancer stem cells (CSCs) promote the potency of tumor initiation. As a result, targeting of glioma stem cells has become the dominant way of improving the therapeutic outcome against GBM and extending the life span of patients. Among the biomarkers of CSCs, CD-133 (prominin-1) has been known to effectively isolate CSCs from cancer population, including GBM; however, the underlying mechanism of how stemness genes manipulate CSC-associated phenotypes, such as tumor initiation and relapse, is still unclear.

Methods: Tumorigenicity, drug resistance and embryonic stem cell markers were examined in primary CD133-positive (CD133(+)) GBM cells and CD133(+) subpopulation. Stemness signature of CD133(+) GBM cells was identified using microarray analysis. Stem cell potency, tumorigenicity and drug resistance were also tested in differential expression of SOX2 in GBM cells.

Results: In this study, high tumorigenic and drug resistance was noticed in primary CD-133(+) GBM cells; meanwhile, plenty of embryonic stem cell markers were also elevated in the CD-133+ subpopulation. Using microarray analysis, we identified SOX2 as the most enriched gene among the stemness signature in CD133(+) GBM cells. Overexpression of SOX2 consistently enhanced the stem cell potency in the GBM cell lines, whereas knockdown of SOX2 dramatically withdrew CD133 expression in CD133(+) GBM cells. Additionally, we silenced SOX2 expression using RNAi system, which abrogated the ability of tumor initiation as well as drug resistance of CD133(+) GBM cells, suggesting that SOX2 plays a crucial role in regulating tumorigenicity in CD133(+) GBM cells.

Conclusion: SOX2 plays a crucial role in regulating tumorigenicity in CD133(+) GBM cells. Our results not only revealed the genetic plasticity contributing to drug resistance and stemness but also demonstrated the dominant role of SOX2 in maintenance of GBM CSCs, which may provide a novel therapeutic target to overcome the conundrum of poor survival of brain cancers.

Keywords: CD133-positive cell; Sox-2; glioblastoma.

MeSH terms

AC133 Antigen / analysis*
Animals
Brain Neoplasms / drug therapy
Brain Neoplasms / pathology*
Cell Line, Tumor
Cell Separation
Drug Resistance, Neoplasm
Female
Glioblastoma / drug therapy
Glioblastoma / pathology*
Humans
Mice
Neoplastic Stem Cells / pathology*
SOXB1 Transcription Factors / analysis
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / physiology*

Substances

AC133 Antigen
PROM1 protein, human
SOX2 protein, human
SOXB1 Transcription Factors