title: 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 years. 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 years. 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 cancer. 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.
authors.affiliation: Department of Biology, University of Rochester, Rochester, New York 14627, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tian
authors.forename: Jorge
authors.initials: J
authors.lastname: Azpurua
authors.forename: Christopher
authors.initials: C
authors.lastname: Hine
authors.forename: Amita
authors.initials: A
authors.lastname: Vaidya
authors.forename: Max
authors.initials: M
authors.lastname: Myakishev-Rempel
authors.forename: Julia
authors.initials: J
authors.lastname: Ablaeva
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Mao
authors.forename: Eviatar
authors.initials: E
authors.lastname: Nevo
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.forename: Andrei
authors.initials: A
authors.lastname: Seluanov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D003260:Contact Inhibition; D060467:Disease Resistance; D005347:Fibroblasts / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000737:chemistry; D006168:Guinea Pigs; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism*; D051379:Mice; D019577:Mole Rats; D008969:Molecular Sequence Data
chemical_list: D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases