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High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat

Nature 499, 346–349 (18 July 2013) | Download Citation

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Abstract

The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum lifespan exceeding 30 years1,2,3. This is the longest reported lifespan for a rodent species and is especially striking considering the small body mass of the naked mole rat. In comparison, a similarly sized house mouse has a maximum lifespan of 4 years4,5. In addition to their longevity, naked mole rats show an unusual resistance to cancer. Multi-year observations of large naked mole-rat colonies did not detect a single incidence of cancer2,6. Here we identify a mechanism responsible for the naked mole rat’s cancer resistance. We found that naked mole-rat fibroblasts secrete extremely high-molecular-mass hyaluronan (HA), which is over five times larger than human or mouse HA. This high-molecular-mass HA accumulates abundantly in naked mole-rat tissues owing to the decreased activity of HA-degrading enzymes and a unique sequence of hyaluronan synthase 2 (HAS2). Furthermore, the naked mole-rat cells are more sensitive to HA signalling, as they have a higher affinity to HA compared with mouse or human cells. Perturbation of the signalling pathways sufficient for malignant transformation of mouse fibroblasts fails to transform naked mole-rat cells. However, once high-molecular-mass HA is removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme, HYAL2, naked mole-rat cells become susceptible to malignant transformation and readily form tumours in mice. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species.

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Change history

  • 17 July 2013

    A minor change was made to the Fig. 4b legend.

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Acknowledgements

This work was supported by the grants from the US National Institutes of Health and Ellison Medical Foundation to V.G. We thank M. Van Meter for critically reading the manuscript.

Author information

    • Xiao Tian
    • , Jorge Azpurua
    •  & Christopher Hine

    These authors contributed equally to this work.

    • Christopher Hine

    Present address: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Affiliations

  1. Department of Biology, University of Rochester, Rochester, New York 14627, USA

    • Xiao Tian
    • , Jorge Azpurua
    • , Christopher Hine
    • , Amita Vaidya
    • , Max Myakishev-Rempel
    • , Julia Ablaeva
    • , Zhiyong Mao
    • , Vera Gorbunova
    •  & Andrei Seluanov

  2. School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, China

    • Zhiyong Mao

  3. Institute of Evolution, University of Haifa, Haifa 31905, Israel

    • Eviatar Nevo

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Contributions

X.T. performed HA analysis, HAase assays, soft agar assays, and generated cells for xenograft experiments; J.A. performed immunoblots and cloning and analysis of HAS2; C.H. identified HA, performed tissue staining, and soft agar assays; A.V. performed xenografts; M.-M.R. performed HA affinity assays; J.A. purified HA; Z.M. performed experiments with HAS2 expression; E.N. provided essential materials; X.T., J.A., C.H., A.S. and V.G. designed the study and analysed data; A.S. and V.G. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Vera Gorbunova or Andrei Seluanov.

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DOI

https://doi.org/10.1038/nature12234

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