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.
Oncogenesis. 2013 Aug 5;2(8):e61. doi: 10.1038/oncsis.2013.23.
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.
SOX2（性别决定区 Y（SRY）-盒 2）在胚胎发育过程中具有重要功能，并且参与癌症干细胞（CSC）的维持，在其中它损害细胞生长和致瘤性。然而，SOX2 在胰腺癌细胞中的功能尚不清楚。本研究的目的是分析 SOX2 在人胰腺肿瘤中的表达，并确定 SOX2 在调节胰腺癌细胞 CSC 特性中的作用。在本报告中，我们表明 SOX2 不在正常胰腺腺泡或导管细胞中表达。然而，在 19.3%的人胰腺肿瘤中观察到 SOX2 的异位表达。SOX2 在胰腺癌细胞中的敲低导致细胞生长抑制，通过与 p21（Cip1）和 p27（Kip1）诱导相关的细胞周期停滞，而 SOX2 的过表达促进 S 期进入和与 cyclin D3 诱导相关的细胞增殖。SOX2 表达与胰腺 CSC 标志物 ALDH1、ESA 和 CD44 的水平增加有关。重要的是，我们表明 SOX2 富集于来自两个不同患者样本的 ESA（+）/CD44（+）CSC 群体中。此外，我们表明 SOX2 直接与 Snail、Slug 和 Twist 启动子结合，导致 E-钙粘蛋白和 ZO-1 表达的丧失。总之，我们的研究结果表明，SOX2 在胰腺癌中异常表达，并通过调节一组控制 G1/S 过渡和上皮-间充质转化（EMT）表型的基因，促进细胞增殖和干细胞/去分化，表明靶向 SOX2 阳性癌细胞可能是一种有前途的治疗策略。
