title: Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity.
abstract: Heparanase activity is highly implicated in cell dissemination associated with tumor metastasis, angiogenesis, and inflammation. Heparanase expression is induced in many hematological and solid tumors, associated with poor prognosis. Heparanase homolog, termed heparanase 2 (Hpa2), was cloned based on sequence homology. Detailed characterization of Hpa2 at the biochemical, cellular, and clinical levels has not been so far reported, and its role in normal physiology and pathological disorders is obscure. We provide evidence that unlike heparanase, Hpa2 is not subjected to proteolytic processing and exhibits no enzymatic activity typical of heparanase. Notably, the full-length Hpa2c protein inhibits heparanase enzymatic activity, likely due to its high affinity to heparin and heparan sulfate and its ability to associate physically with heparanase. Hpa2 expression was markedly elevated in head and neck carcinoma patients, correlating with prolonged time to disease recurrence (follow-up to failure; p = 0.006) and inversely correlating with tumor cell dissemination to regional lymph nodes (N-stage; p = 0.03). Hpa2 appears to restrain tumor metastasis, likely by attenuating heparanase enzymatic activity, conferring a favorable outcome of head and neck cancer patients.
authors.affiliation: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Flonia
authors.initials: F
authors.lastname: Levy-Adam
authors.forename: Sari
authors.initials: S
authors.lastname: Feld
authors.forename: Victoria
authors.initials: V
authors.lastname: Cohen-Kaplan
authors.forename: Anna
authors.initials: A
authors.lastname: Shteingauz
authors.forename: Miriam
authors.initials: M
authors.lastname: Gross
authors.forename: Gil
authors.initials: G
authors.lastname: Arvatz
authors.forename: Inna
authors.initials: I
authors.lastname: Naroditsky
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.forename: Ilana
authors.initials: I
authors.lastname: Doweck
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D011485:Protein Binding; D021381:Protein Transport; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D006497:Heparan Sulfate; D000099175:Heparanase