Hyaluronan: An Architect and Integrator for Cancer and Neural Diseases

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• Hyaluronan (HA) is crucial for cell physiology, but its size and conformation under different conditions and their functional relevance remain unclear.
• Understanding HA's interactions with proteins and its matrix properties is key to deciphering its role in health and disease.

Purpose of the Study:

• To update knowledge on hyaluronan functional properties, including binding proteins, signaling networks, and matrix formation.
• To elucidate the distinct signaling outcomes of HA interactions with membrane receptors versus GPI-linked hyaluronidase Hyal-2.
• To explore the role of HA in inflammation, Alzheimer's disease, cancer suppression, and neurodegeneration retardation.

Main Methods:

• Review and synthesis of existing literature on hyaluronan structure, function, and interactions.
• Analysis of signaling pathways involving HA, its receptors, and associated proteins like HYAL-2, WWOX, and SMAD4.
• Discussion of HA's role in matrix formation, phase separation, and its implications in disease.

Main Results:

• Native, large HA is not inherently proapoptotic; however, overexpression of HYAL-2/WWOX/SMAD4 complex with HA can induce apoptosis in inflamed microenvironments.
• HA-binding proteins form interconnected signaling networks, with competitive binding between HA and TGF-β to HYAL-2 influencing downstream signaling.
• HA matrices can undergo phase separation, affecting molecular mobility and potentially driving aberrant interactions in inflammation and disease.
• HA and complement C1q are implicated in Alzheimer's disease through WWOX, a known risk factor.
• Inducible conformational changes in HA exhibit cancer-suppressive and neuroprotective effects.

Conclusions:

• Hyaluronan's biological outcomes are highly dependent on its size, conformation, and interaction partners, particularly in inflamed states.
• Dysregulation of HA-related signaling pathways, including HYAL-2/WWOX/SMAD4, contributes to disease pathogenesis.
• HA's matrix properties and conformational plasticity offer potential therapeutic targets for cancer and neurodegenerative diseases.