title: Heparanase augments inflammatory chemokine production from colorectal carcinoma cell lines.
abstract: To explore possible roles of heparanase in cancer-host crosstalk, we examined whether heparanase influences expression of inflammatory chemokines in colorectal cancer cells. Murine colorectal carcinoma cells incubated with heparanase upregulated MCP-1, KC, and RANTES genes and released MCP-1 and KC proteins. Heparanase-dependent production of IL-8 was detected in two human colorectal carcinoma cell lines. Addition of a heparanase inhibitor Heparastatin (SF4) did not influence MCP-1 production, while both latent and mature forms of heparanase augmented MCP-1 release, suggesting that heparanase catalytic activity was dispensable for MCP-1 production. In contrast, addition of heparin to the medium suppressed MCP-1 release in a dose-dependent manner. Similarly, targeted suppression of Ext1 by RNAi significantly suppressed cell surface expression of heparan sulfate and MCP-1 production in colon 26 cells. Taken together, it is concluded that colon 26 cells transduce the heparanase-mediated signal through heparan sulfate binding. We propose a novel function for heparanase independent of its endoglycosidase activity, namely as a stimulant for chemokine production.
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsunekawa
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; One-stop Sharing Facility Center for Future Drug Discoveries, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: higashi@mol.f.u-tokyo.ac.jp.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Higashi
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kogane
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Michihiko
authors.initials: M
authors.lastname: Waki
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shida
authors.affiliation: Institute of Microbial Chemistry, Tokyo, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Institute of Microbial Chemistry, Tokyo, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021, Japan.
authors.forename: Hayamitsu
authors.initials: H
authors.lastname: Adachi
authors.affiliation: SBI Pharmaceuticals Co., Ltd., 1-6-1, Roppongi, Minato-ku, Tokyo 106-6019, Japan.
authors.forename: Motowo
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Biochemistry and Department of Breast and Endocrine Surgery, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 104-8560, Japan. Electronic address: t-irimura@juntendo.ac.jp.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Irimura
mesh_terms: D002384:Catalysis; D045744:Cell Line, Tumor; D018925:Chemokines / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000276:immunology*; D004789:Enzyme Activation; D005966:Glucuronidase / Q000276:immunology*; D006497:Heparan Sulfate / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D000099175:Heparanase
chemical_list: D018925:Chemokines; D005966:Glucuronidase; D006497:Heparan Sulfate; D058847:Inflammasomes; D000099175:Heparanase
keywords: Chemokine; Colorectal carcinoma; Heparan sulfate; Heparanase