title: Antitumor effects of 4-methylumbelliferone, a hyaluronan synthesis inhibitor, on malignant peripheral nerve sheath tumor.
abstract: Hyaluronan (HA) has been shown to play important roles in the growth, invasion and metastasis of malignant tumors. Our previous study showing that high HA expression in malignant peripheral nerve sheath tumors (MPNST) is predictive of poor patient prognosis, prompted us to speculate that inhibition of HA synthesis in MPNST might suppress the tumorigenicity. The aim of our study was to investigate the antitumor effects of 4-methylumbelliferone (MU), an HA synthesis inhibitor, on human MPNST cells and tissues. The effects of MU on HA accumulation and tumorigenicity in MPNST cells were analyzed in the presence or absence of MU in an in vitro as well as in vivo xenograft model using human MPNST cell lines, sNF96.2 (primary recurrent) and sNF02.2 (metastatic). MU significantly inhibited cell proliferation, migration and invasion in both MPNST cell lines. HA binding protein (HABP) staining, particle exclusion assay and quantification of HA revealed that MU significantly decreased HA accumulation in the cytoplasms and pericellular matrices in both MPNST cell lines. The expression levels of HA synthase2 (HAS2) and HA synthase3 (HAS3) mRNA were downregulated after treatment with MU. MU induced apoptosis of sNF96.2 cells, but not sNF02.2 cells. MU administration significantly inhibited the tumor growth of sNF96.2 cells in the mouse xenograft model. To the best of our knowledge, our study demonstrates for the first time the antitumor effects of MU on human MPNST mediated by inhibition of HA synthesis. Our results suggest that MU may be a promising agent with novel antitumor mechanisms for MPNST.
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine 65, Nagoya, 466-8550, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Ikuta
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine 65, Nagoya, 466-8550, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Ota
authors.affiliation: Advanced Medical Research center and Multidisciplinary Pain Center, Aichi Medical University, Nagakute, 480-1195, Japan.
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhuo
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine 65, Nagoya, 466-8550, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Urakawa
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine 65, Nagoya, 466-8550, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kozawa
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine 65, Nagoya, 466-8550, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Hamada
authors.affiliation: Advanced Medical Research center and Multidisciplinary Pain Center, Aichi Medical University, Nagakute, 480-1195, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine 65, Nagoya, 466-8550, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School and School of Medicine 65, Nagoya, 466-8550, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nishida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism*; D006923:Hymecromone / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D006923:Hymecromone; D006820:Hyaluronic Acid
keywords: 4-methylumbeliferone; hyaluronan; malignant peripheral nerve sheath tumor; neurofibromatosis Type 1