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Bioengineered tumor microenvironments with naked mole rats high-molecular-weight hyaluronan induces apoptosis in breast cancer cells

Oncogene (2019) | Download Citation

Abstract

The naked mole rat (nmr) is cancer resistant due to the abundant production of extremely high-molecular-weight hyaluronan (EHMW-HA). However, whether EHMW-HA has similar anti-cancer effects in mice and humans remains to be determined. The present study used breast cancer cells to clarify the effect of EHMW-HA on breast cancer. First, the overexpression of nmrHas2 in 4T1 and BT549 cell lines in both two-dimensional (2D) and three-dimensional (3D) models to mimic tumor microenvironment was established. The 4T1/BT549-nmrHas2 cells could secrete EHMW-HA (with a molecular weight of up to 6 MDa), which was similar to that found in the naked mole rat. Second, EHMW-HA altering tumor microenvironment in both 2D monolayers and 3D spheroids significantly enhanced apoptosis, inhibiting the proliferation of 4T1 and BT549 cells. The prominent anticancer effects of EHMW-HA on the cancer-cell apoptosis phenotype were further confirmed by inhibiting tumor formation in nude mice. Finally, EHMW-HA significantly induced higher p53 protein expression, which enhanced pro-apoptotic proteins p21 and Bax in breast cancer cells; this is in contrast with the triggering of hypersensitivity of the naked mole rat cells to early contact inhibition (ECI). These results have important implications for the design of therapeutic approaches based on the application of EHMW-HA.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (Grant No.: 51773050 and 81770923), the Opening Foundation of the State Key Laboratory of Cancer Biology (CBSKL201106), and the author was supported by the Heilongjiang Postdoctoral Fund (No. LBH-Z18068) and a general financial grant from the China Postdoctoral Science Foundation (No. 2018M641837).

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Author notes

  1. These authors contributed equally: Yufang Zhao, Shupei Qiao

Affiliations

  1. School of Life Science and Technology, Harbin Institute of Technology, 150080, Harbin, China

    • Yufang Zhao
    • , Shupei Qiao
    • , Xiaolu Hou
    • , Hui Tian
    • , Shuai Deng
    • , Kangruo Ye
    •  & Weiming Tian
  2. Research Center of Basic Space Science, Space Environment Stimulation and Research Interface, Harbin Institute of Technology, 150080, Harbin, China

    • Yufang Zhao
  3. State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 150080, Harbin, China

    • Yongzhan Nie
  4. Department of Mechanical Engineering, University of Saskatchewan, Saskatoon, SK S7N 5A2, Canada

    • Xiongbiao Chen
  5. Division of Glycoscience, Department of Chemistry, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTHRoyal Institute of Technology, AlbaNova University Center, 106 91, Stockholm, Sweden

    • Hongji Yan

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Correspondence to Weiming Tian.

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DOI

https://doi.org/10.1038/s41388-019-0719-4