title: SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells.
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.
authors.affiliation: 1] Division of Oncology Research, Schulze Center for Novel Therapeutics, College of Medicine, Mayo Clinic, Rochester, MN, USA [2] Department of Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco UPV/EHU, San Sebastián, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Herreros-Villanueva
authors.forename: J-S
authors.initials: JS
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Koenig
authors.forename: E V
authors.initials: EV
authors.lastname: Abel
authors.forename: T C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: W R
authors.initials: WR
authors.lastname: Bamlet
authors.forename: A A-M
authors.initials: AA
authors.lastname: de Narvajas
authors.forename: T S
authors.initials: TS
authors.lastname: Gomez
authors.forename: D M
authors.initials: DM
authors.lastname: Simeone
authors.forename: L
authors.initials: L
authors.lastname: Bujanda
authors.forename: D D
authors.initials: DD
authors.lastname: Billadeau
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