title: Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.affiliation: Division of Colorectal Surgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Chi-Shuan
authors.initials: CS
authors.lastname: Huang
authors.affiliation: Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Wei-Hsiu
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Wai-Wah
authors.initials: WW
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Yi-Yen
authors.initials: YY
authors.lastname: Lee
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Lo
authors.affiliation: Division of Gastroenterology, Cheng-Hsin General Hospital, Taipei, Taiwan, ROC; School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, ROC; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Ming-Teh
authors.initials: MT
authors.lastname: Chen
mesh_terms: D000071916:AC133 Antigen / Q000032:analysis*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D055748:SOXB1 Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*
chemical_list: D000071916:AC133 Antigen; C000606023:PROM1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
keywords: CD133-positive cell; Sox-2; glioblastoma