Abstract
Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3− CD19− Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.
Highlights
High molecular weight hyaluronan (HA) is accounted for approximately 0.02% of a human body weight (e.g., 16 g HA in an 80 kg individual), in which one third of the amount undergoes daily turnover (Stern, 2004; Viola et al, 2015; Chanmee et al, 2016)
We have shown that TGF-β1 binds membrane HYAL-2, followed by internalization of the resulting TGF-β1/HYAL-2 complexes by endosomes and fusion with lysosomes (Hsu et al, 2009)
Activated Z cells recognize many types of cancer cells, suggesting that there is a common antigen in the polymerized Zfra, which shares structural similarity with antigens on the surface of cancer cells
Summary
High molecular weight hyaluronan (HA) is accounted for approximately 0.02% of a human body weight (e.g., 16 g HA in an 80 kg individual), in which one third of the amount undergoes daily turnover (Stern, 2004; Viola et al, 2015; Chanmee et al, 2016). It is generally believed that high molecular weight HA provides a space-filling function for tissues and organs (Lee and Spicer, 2000) In this case, HA is strong in anti-inflammation, anti-angiogenesis and anti-cancer growth, and supports wound healing (Tian et al, 2013; Tolg et al, 2014; Schwertfeger et al, 2015; Litwiniuk et al, 2016). Low molecular weight HA is capable of stimulating angiogenesis, provoking proinflammation, and supporting cancer growth (Tian et al, 2013; Schwertfeger et al, 2015; Litwiniuk et al, 2016). Due to the altered conformation and reduced sizes, HA is able to achieve a great potency in anti-inflammation and blocking cancer growth (Chang and Su, 2016)
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