Physiological ?-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma.

ABSTRACT:

Background

A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/?-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological ?-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of ?-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells.

Results

Introduction of increased ?-catenin signaling, haploid expression of ?-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/?-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous ?-catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24(+) and CD44(+) populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4-mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/?-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-?, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using ?-catenin shRNA inhibitory assays, a dominant role for ?-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres.

Conclusions

Wnt/?-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/?-catenin signaling with stemness transition networks.

SUBMITTER: Cheng Y 

PROVIDER: S-EPMC3819748 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature