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

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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.

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  • 17 July 2013

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


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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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Authors and Affiliations



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).

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