title: HYAL-2-WWOX-SMAD4 Signaling in Cell Death and Anticancer Response.
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-2deficiency 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 cellsin 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.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University Tainan, Taiwan.
authors.forename: Li-Jin
authors.initials: LJ
authors.lastname: Hsu
authors.affiliation: Department of Neurosurgery, Mackay Memorial Hospital, Mackay Medicine, Nursing and Management College, and Graduate Institute of Injury Prevention and Control, Taipei Medical University Taipei, Taiwan.
authors.forename: Ming-Fu
authors.initials: MF
authors.lastname: Chiang
authors.affiliation: Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Chun-I
authors.initials: CI
authors.lastname: Sze
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Wan-Pei
authors.initials: WP
authors.lastname: Su
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Ye Vone
authors.initials: YV
authors.lastname: Yap
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: I-Ting
authors.initials: IT
authors.lastname: Lee
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University Tainan, Taiwan.
authors.forename: Hsiang-Ling
authors.initials: HL
authors.lastname: Kuo
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung UniversityTainan, Taiwan; Advanced Optoelectronic Technology Center, National Cheng Kung UniversityTainan, Taiwan; Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung UniversityTainan, Taiwan; Department of Neurochemistry, New York State Institute for Basic Research in Developmental DisabilitiesStaten Island, NY, USA; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical UniversityTaichung, Taiwan.
authors.forename: Nan-Shan
authors.initials: NS
authors.lastname: Chang
keywords: HYAL-2; Z cell; Zfra; cancer; hyaluronan; hyaluronidase; prevention; treatment