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Recent Research Progress
HYAL1, a hyaluronidase able to degrade the glycosaminoglycans hyaluronic acid (HA) and chondroitin sulfate, is upregulated upon osteoclastogenesis. The findings point out the predominant involvement of HYAL1 in bone HA metabolism and perhaps bone remodeling via the resorption lacuna. Furthermore, the expression of HYAL1 is strongly upregulated, at the mRNA and protein level, upon in vitro differentiation of macrophages into osteoclasts. In addition, it is reported that the osteoclast differentiation process includes changes in the subcellular trafficking of HYAL1 that promote its extracellular residency.
HYAL1 catalyzes the hydrolysis of chondroitin sulfate and binds to chondroitin sulfate proteoglycans such as integrins and other cell surface receptors, so its direct binding is another way in which active HYAL1 may affect cell surface receptor involvement. Specially, HYAL1 may adhere to the surface of the exosome, primarily to promote its cell docking, allowing exosome contents to be delivered to target cells more efficiently. Upon internalization, changes in the vesicle microenvironment may lead to dissociation of HYAL1, and then exosome residues can participate in the subsequent process independently of HYAL1.
What is particularly noteworthy is that HYAL1 expression in tumor cells can influence cancer progression. 22Rv1 cells that over-express HYAL1 are more rapidly metastatic than control cells. HYAL1 is secreted as a soluble factor by the cell, and since its activity requires low pH, it could be locally active within acidic microenvironments at the tumor site. Presence of HYAL1 in exosomes implies that it could also be carried from the primary tumor site through the lymphatics or the circulation and arrive at target cells in remote tissues. In this way, a tumor over-expressing HYAL1 could initiate events to prepare tissues for metastasis. According to the recent research, higher HYAL1 expression was detected among primary tumors from patients with subsequent brain metastases compared with those without brain metastases. Interestingly, brain metastatic tissue showed a significantly reduced HYAL1 expression compared with the corresponding primary tumor. HYAL1 expression in brain metastases was also significantly lower than in skin, liver, and lung metastases. Some results suggest that the enzyme HYAL1 plays a role in tumor dissemination and brain-specific colonization, rather than in subsequent metastatic out-growth.
Coincidentally, the hyaluronidase HYAL1 is clinically and functionally implicated in prostate cancer progression and metastasis. Elevated HYAL1 accelerates vesicular trafficking in prostate tumor cells, thereby enhancing their metastatic potential in an autocrine manner through increased motility and proliferation. HYAL1 protein is a component of exosomes produced by prostate tumor cell lines. The presence of HYAL1 in tumor-derived exosomes and its ability to impact the behavior of stromal cells suggests cell-cell communication via exosomes is a novel mechanism by which elevated HYAL1 promotes prostate cancer progression. Prostate tumor cells over-expressing HYAL1 had accelerated vesicular trafficking rates that increased autocrine proliferation and movement through changes in cell surface integrins and cadherins.
What’s more, the expression of HYAL1 is increased in pancreatic ductal adenocarcinoma (PDAC). Screening of mRNA expression genes identified HYAL1 as a gene over-expressed in PDAC cells, suggesting that epigenetic mechanisms may be involved in the transcriptional regulation of this gene. HYAL1 protein concentrations were significantly higher in primary PDAC tissues as compared with non-tumor pancreatic tissues. Importantly, inhibition of HYAL by dextran sulfate significantly inhibited the migration of PDAC cells and shown strong HYAL1 expression. In other words, these findings suggest that over-expression of HYAL1 is a common mechanism that may contribute to the aggressive phenotype of PDAC.