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MiR-26a inhibits stem cell-like phenotype and tumor growth of osteosarcoma by targeting Jagged1

Oncogene volume 36, pages 231–241 (2017)Cite this article

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Abstract

MicroRNAs (miRNAs) are important epigenetic regulators of gene expression. Although several miRNAs have been implicated in osteosarcoma, their role in regulation of osteosarcoma cancer stem cells (CSCs) remains unknown. Here we demonstrated that miR-26a is downregulated in osteosarcoma CSCs when derived by either sarcosphere generation, chemodrug or aldehyde dehydrogenase (ALDH) activity selection. Lentiviral overexpression of miR-26a in ZOS and 143B osteosarcoma cells decreases the expression of stem cell markers and suppresses sarcosphere formation, as well as ALDH activity. Moreover, miR-26a overexpression inhibits the tumor cell growth both in vitro and in vivo. We further demonstrate that miR-26a directly target Jagged1, one of the Notch ligand, and that its tumor suppressive effects are mediated through inhibition of Jagged1/Notch signaling. Importantly, reduced miR-26a expression, as determined by in situ hybridization in patient tumors (n=92), is associated with lung metastasis and poor overall survival of osteosarcoma patients. Together, these data suggest the essential role of miR-26a/Jagged1/Notch pathway in regulating the stem cell-like traits of osteosarcoma cells and provide a potential target for osteosarcoma therapy.

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Acknowledgements

This research was supported by National Natural Science Foundation of China (81272939 and 81472506 to JS) and Natural Science Foundation of Guangdong Province (S2013020012460 to JS). D-FL is the Cancer Prevention Research Institute of Texas (CPRIT) scholar in Cancer Research and supported by National Institutes of Health (NIH) Pathway to Independence Award R00 CA181496 and CPRIT Award RR160019. We thank Jingling Zhao (Sun Yat-Sen University) for expert technical assistance and Meghan Lambie (University of Toronto) for language editing.

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Author notes

  1. J Lu and G Song: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    J Lu, G Song, Q Tang, J Yin, C Zou, Z Zhao, X Xie, H Xu, G Huang, J Wang & J Shen

  2. Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, USA

    D-F Lee

  3. Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    R Khokha

  4. Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China

    H Yang

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Correspondence to H Yang or J Shen.

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Lu, J., Song, G., Tang, Q. et al. MiR-26a inhibits stem cell-like phenotype and tumor growth of osteosarcoma by targeting Jagged1. Oncogene 36, 231–241 (2017). https://doi.org/10.1038/onc.2016.194

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