Hyaluronan: molecular size‐dependent signaling and biological functions in inflammation and cancer

Abstract

Hyaluronan (HA) is a linear nonsulfated glycosaminoglycan of the extracellular matrix that plays a pivotal role in a variety of biological processes. High‐molecular weight HA exhibits different biological properties than oligomers and low‐molecular weight HA. Depending on their molecular size, HA fragments can influence cellular behavior in a different mode of action. This phenomenon is attributed to the different manner of interaction with the HA receptors, especially CD44 and RHAMM. Both receptors can trigger signaling cascades that regulate cell functional properties, such as proliferation migration, angiogenesis, and wound healing. HA fragments are able to enhance or attenuate the HA receptor‐mediated signaling pathways, as they compete with the endogenous HA for binding to the receptors. The modulation of these pathways could be crucial for the development of pathological conditions, such as inflammation and cancer. The primary goal of this review is to critically present the importance of HA molecular size on cellular signaling, functional cell properties, and morphology in normal and pathological conditions, including inflammation and cancer. A deeper understanding of these mechanisms could contribute to the development of novel therapeutic strategies.

Emerging roles for UDP-glucuronosyltransferases in drug resistance and cancer progression

“…HA possesses structural and cell-signalling functions that can affect the metastatic process by facilitating cell-cell signalling and motility. 91 Enhanced HA levels confer an unfavourable prognosis (aggressive phenotypes and reduced survival) in several cancer types (reviewed in ref. 92 ).…”

Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-κB and expression of the long-noncoding RNA HAS2–AS1

“…HASes are very unusual proteins as they are transported to the plasma membrane where they are able to form homo and heterodimers and are activated to extrude the nascent HA chain into the extracellular space (23). In physiological conditions, HAS1 and HAS2 synthesize HA polymers of high molecular mass, while HAS3 synthesizes shorter HA polymers (24), and the production of low molecular mass HA can be obtained by the action of degrading enzymes as well as by oxidative stress or ultraviolet light (25,26). Interestingly, the stoichiometry of the cytosolic UDP substrates has a critical role to define HA polymer length, and the C-terminal region of HASes appears to have regulatory functions (27).…”

Knockdown Of Udp-Glucose Dehydrogenase Facilitates Epirubicin-Resistance In MDA-MB-231 Breast Cancer Cells By Regulation Of Hyaluronan Synthesis.

“…Conversely, we observed less increase in HAS-2 expression in accordance with a slight modulation of soluble HA levels. Besides, it would be interesting to study the molecular weight of HA produced by tumor cells, since it can have differentiated functions [22]. Furthermore, the unexpected increase in HYALs expression considering higher pericellular area could be explained taking into account that, in the absence of UGDH enzyme, breast cancer cells require a new source of UDP-GlcUA to synthesize HA (and other GAGs and PGs).…”

“…In cancer development it is well known that HA expression is usually altered, affecting several mechanisms associated, among others, with cell proliferation and survival, invasion, angiogenesis and multidrug resistance, [19][20][21][22][23][24]. Even more, it has been recently demonstrated that HA also affects immune cells recruitment and in ammation [25].…”