Abstract 420: Physiological β-catenin signaling regulates pluripotency genes in cancer microcell hybrids

Abstract

Abstract Both β-catenin signaling and Nanog were previously reported to be involved in cell fusion-mediated somatic cell reprogramming. It remains unclear as to how the β-catenin signaling pathway is initiated and whether this pathway may directly control the expression of core stem cell factors such as Nanog and Oct4. Since β-catenin signaling is a predominating force for the regulation of cellular fate and basic levels of this signaling are needed for somatic cell reprogramming, we speculate that transfer of a single copy of chromosome 3, where β-catenin maps and is controlled by its natural regulators, into somatic cancer cells may appropriately induce this pathway and switch on the expression of endogenous pluripotency genes in recipient cells. We previously generated human nasopharyngeal (HONE1) and esophageal (SLMT1) carcinoma hybrid cells with an intact copy of transferred chromosome 3. At both transcriptional and translational levels, we detected obvious expression of genes related to the Wnt/β-catenin pathway in HONE1/chromosome 3 hybrid cells. In these hybrid cells, β-catenin, c-Myc, Axin2, Tcf1, Sox2, Klf4, Oct4, and Nanog were either strongly expressed or up-regulated. The loss of region that contains B-catenin locus in transferred chromosome 3 abolishes the expression of core stem cell genes. The control of these gene activities by physiological β-catenin signaling was further confirmed in HONE1/chromosome 17 hybrids that contain the downstream components of β-catenin signaling Axin2 and Stat3, but was not detected in hybrids with an irrelevant transferred chromosome and SLMT1 cells that had a relatively high level of endogenous β-catenin expression. We also found that HONE1 hybrid cells have stem cell-like properties, including spheroid formation, up-regulation of CD24+ and CD44+ populations and expression of various embryonic markers. Additionally, chromosome 3 transfer induced epithelial-mesenchymal transformation (EMT) events in HONE1 cells that caused different expression of adhesion molecules and up-regulation of their regulators and other markers such as Twist, Snail, Slug, ZEB1, Sip1, and E-cadherin. As expected, we detected that p53, Rb1, and Smad2 involved pathways were activated in HONE1 hybrid cells, suggesting that physiological β-catenin signaling, via multiple signaling pathways, regulates both pluripotency networks and EMT events. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 420. doi:1538-7445.AM2012-420