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

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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Figure 1: Naked mole-rat cells secrete HA of exceptionally high molecular mass.
Figure 2: Naked mole-rat tissues contain high levels of HA.
Figure 3: HMM-HA is required for ECI.
Figure 4: Removal of HMM-HA makes naked mole-rat cells susceptible to malignant transformation.

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.

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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.

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Correspondence to Vera Gorbunova or Andrei Seluanov.

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The authors declare no competing financial interests.

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Tian, X., Azpurua, J., Hine, C. et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499, 346–349 (2013). https://doi.org/10.1038/nature12234

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