Abstract
Hyaluronan (HA) is a simple but diverse glycosaminoglycan. It plays a major role in aging, cellular senescence, cancer, and tissue homeostasis. In which way HA affects the surrounding tissues greatly depends on the molecular weight of HA. Whereas high molecular weight HA is associated with homeostasis and protective effects, HA fragments tend to be linked to the pathologic state. Furthermore, the interaction of HA with its binding partners, the hyaladherins, such as CD44, is essential for sustaining tissue integrity and is likewise related to cancer. The naked mole rat, a rodent species, possesses a special form of very high molecular weight (vHMW) HA, which is associated with the extraordinary cancer resistance and longevity of those animals. This review addresses HA and its diverse facets: from HA synthesis to degradation, from oligomeric HA to vHMW-HA and from its beneficial properties to the involvement in pathologies. We further discuss the functions of HA in the naked mole rat and compare them to human conditions. Though intensively researched, this simple polymer bears some secrets that may hold the key for a better understanding of cellular processes and the development of diseases, such as cancer.
Highlights
Specialty section: This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology
Whereas high molecular weight HA is associated with homeostasis and protective effects, HA fragments tend to be linked to the pathologic state
The naked mole rat, a rodent species, possesses a special form of very high molecular weight HA, which is associated with the extraordinary cancer resistance and longevity of those animals
Summary
Hypersensitivity to contact inhibition is one of the unique properties of naked mole rats: they show the so-called early contact inhibition (ECI). Mammalian tumor suppressors: the cyclin-dependent kinase inhibitors p15INK4b (p15) and p16INK4a (p16) as well as p19ARF (p19), a repressor of the MDM2 oncogene Out of those tumor suppressors, the level of p16 is elevated in naked mole rat cells that exhibit ECI [38, 42]. While the contact inhibition in humans or mice is primarily mediated by the p27 cyclin-dependent kinase inhibitor; in naked mole rats, this suppressor seems to only serve as a backup if the ECI is not functional [38]. In addition to the upregulation of p16, a fourth unique product of the INK4a/b locus has been found in naked mole rats This isoform, pALTINK4a/b, is capable of arresting the cell cycle more efficiently than the other INK4a/b suppressors and does so independently of HA–CD44 interactions [42]. Detailed investigation of the causes and documentation of such rare cases will benefit the current cancer research and increase recent knowledge concerning cancer resistance mechanisms
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