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 p21Cip1 and p27Kip1 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.

Electron microscopic analysis of different cell types in human pancreatic cancer spheres

“…In this study, we used serum-containing medium because PANC-1 cells most rapidly form large spheres under these conditions. The spheres generated from these cells expressed high mRNA levels of CSC markers, suggesting that they contain CSCs (7,13,(17)(18)(19). A previous study showed that PANC-1 cells grown in a serum-containing medium formed clusters that were heterogeneous for dye efflux, while cells grown in the serum-free medium with supplements commonly used to culture stem cells gave rise to colonies that varied in their ability to efflux dye and respond to verapamil (27).…”

“…To confirm the stemness of the PANC-1 spheres, we screened the spheres for expression of CSC markers, including Oct4, sex determining region Y-box 2 (Sox2), nestin, CD24, and CD44v9 (7,(17)(18)(19). Notably, the mRNA expression level of each of these markers was higher in PANC-1 spheres than in adherent cells ( Fig.…”

Physcion inhibits the metastatic potential of human colorectal cancer SW620 cells in vitro by suppressing the transcription factor SOX2

“…Interestingly, strong SOX2 expression is associated with many types of human solid tumors, including lung cancer, breast cancer, ovarian carcinoma, pancreatic carcinoma and esophageal carcinoma [7] . Furthermore, recent studies have shown that SOX2 is involved in the biological behaviors of a variety of human malignancies, including proliferation [8] , apoptosis [9,10] , and invasion and metastasis [7] . In terms of CRC, the increased expression of SOX2 is associated with distant metastases and lymph-node metastases in rightsided CRC [11] .…”

Differential effects of Akt isoforms on somatic cell reprogramming

“…Additionally, the short duration of iPSC generation (2-3 weeks) provides a convenient way to study mechanisms of cellular dedifferentiation, a process also associated with tumor development and metastasis (Gabbert et al, 1985;Herreros-Villanueva et al, 2013;Schwitalla et al, 2013;Zhang et al, 2013). iPSCs can be induced by ectopic expression of different sets of transcription factors, e.g.…”