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CD58, a novel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer

Oncogene volume 34, pages 1520–1531 (2015)Cite this article

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Abstract

Colorectal tumor-initiating cells (CT-ICs) have self-renewal capabilities and have an important role in tumorigenesis, metastasis, recurrence and treatment resistance in colorectal cancer. Multiple cell-surface molecules targeting CT-ICs, possibly representing different CT-IC subpopulations, have been reported. However, whether new surface markers exist, as well as the mechanisms by which the markers regulate self-renewal, remain unclear. In this study, we enriched a CT-IC population through a serum-free low-adhesion system in vitro. Within this population, we found that CD58 and CD44 were upregulated using a cDNA GeneChip, and CD44highCD58high cancer cells, the common existence of which was demonstrated by flow cytometry in multiple colon cancer cell lines and primary specimens, exhibited enhanced self-renewal ability, epithelial–mesenchymal transition ability and tumorigenicity, both in vitro and in vivo. Furthermore, activated CD58 upregulated the Wnt/β-catenin pathway and thus promoted self-renewal of CT-ICs; conversely, knockdown of CD58 significantly impaired sphere formation and tumor growth. With immunoprecipitation and western blotting approaches, CD58 was found to upregulate the Wnt pathway by degradation of Dickkopf 3. These results indicate that CD58 is a novel cell-surface marker that functionally regulates self-renewal of CT-ICs, which may provide an intriguing therapeutic target for the efficient killing and elimination of CT-ICs.

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Acknowledgements

We thank Mr Qinghua Lu (Cancer Institute and Education Ministry Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine) for FCM analysis. This work was supported by grants from the National Science of Foundation Committee of China (81071768, 81071619, 31090361, 81372348), the Natural Science of Foundation of Zhejiang Province (R2090074, Y2110246) and the Foundation of Scientific Technology Bureau of Zhejiang Province (2010C33118, 2011C23091, 2013C33129).

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  1. S Xu and Z Wen: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Gastroenterology, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, China

    S Xu, Z Wen, L Zhu, S Feng, Y Zhao, J Wu, J Mao & Y Zhu

  2. Department of Gastroenterology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China

    Q Jiang

  3. Cancer Institute and Education Ministry Key Laboratory of Cancer Prevention and Intervention, School of Medicine, Zhejiang University, Hangzhou, China

    Q Dong & Y Zhu

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Correspondence to Y Zhu.

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Xu, S., Wen, Z., Jiang, Q. et al. CD58, a novel surface marker, promotes self-renewal of tumor-initiating cells in colorectal cancer. Oncogene 34, 1520–1531 (2015). https://doi.org/10.1038/onc.2014.95

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