SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells

M. Herreros-Villanueva, J. S. Zhang, A. Koenig, E. V. Abel, T. C. Smyrk, W. R. Bamlet, A. A.M. De Narvajas, T. S. Gomez, D. M. Simeone, L. Bujanda, D. D. Billadeau

Research output: Contribution to journalArticle

187 Scopus citations

Abstract

SOX2 (Sex-determining region Y (SRY)-Box2) has important functions during embryonic development and is involved in cancer stem cell (CSC) maintenance, in which it impairs cell growth and tumorigenicity. However, the function of SOX2 in pancreatic cancer cells is unclear. The objective of this study was to analyze SOX2 expression in human pancreatic tumors and determine the role of SOX2 in pancreatic cancer cells regulating CSC properties. In this report, we show that SOX2 is not expressed in normal pancreatic acinar or ductal cells. However, ectopic expression of SOX2 is observed in 19.3% of human pancreatic tumors. SOX2 knockdown in pancreatic cancer cells results in cell growth inhibition via cell cycle arrest associated with p21 Cip1 and p27 Kip1 induction, whereas SOX2 overexpression promotes S-phase entry and cell proliferation associated with cyclin D3 induction. SOX2 expression is associated with increased levels of the pancreatic CSC markers ALDH1, ESA and CD44. Importantly, we show that SOX2 is enriched in the ESA+/CD44 + CSC population from two different patient samples. Moreover, we show that SOX2 directly binds to the Snail, Slug and Twist promoters, leading to a loss of E-Cadherin and ZO-1 expression. Taken together, our findings show that SOX2 is aberrantly expressed in pancreatic cancer and contributes to cell proliferation and stemness/dedifferentiation through the regulation of a set of genes controlling G1/S transition and epithelial-to-mesenchymal transition (EMT) phenotype, suggesting that targeting SOX2-positive cancer cells could be a promising therapeutic strategy.

Original languageEnglish (US)
Article numbere61
JournalOncogenesis
Volume2
DOIs
StatePublished - 2013

Keywords

  • SOX2
  • cancer stem cells
  • pancreatic cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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    Herreros-Villanueva, M., Zhang, J. S., Koenig, A., Abel, E. V., Smyrk, T. C., Bamlet, W. R., De Narvajas, A. A. M., Gomez, T. S., Simeone, D. M., Bujanda, L., & Billadeau, D. D. (2013). SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells. Oncogenesis, 2, [e61]. https://doi.org/10.1038/oncsis.2013.23