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

BMC Cell Biology

Maria Li Lung¹  Marian L Waterman²  Paulisally Hau Yi Lo¹  Pui Man Chiu¹  Yee Peng Phoon¹  Josephine Mun Yee Ko¹  Arthur Kwok Leung Cheung¹  Yue Cheng¹ 

[1] Department of Clinical Oncology, Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, L6-02, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China;Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697, USA

关键词: Cancer stem cell markers;    Tumor suppressor genes;    Stemness transition;    Chromosome 3 transfer;    Self-renewal network;    Nasopharyngeal carcinoma;    Physiological Wnt/β-catenin signaling;   

Others  :  856550
DOI  :  10.1186/1471-2121-14-44

 received in 2013-04-05, accepted in 2013-09-25,  发布年份 2013

【 摘 要 】

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/β-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological β-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of β-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 β-catenin signaling, haploid expression of β-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/β-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous β-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/β-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-β, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using β-catenin shRNA inhibitory assays, a dominant role for β-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/β-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/β-catenin signaling with stemness transition networks.

【 授权许可】

   
2013 Cheng et al.; licensee BioMed Central Ltd.

【 图 表 】

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