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 fulllength 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.

Common cancer in a wild animal: the California sea lion ( Zalophus californianus ) as an emerging model for carcinogenesis

“…In humans, the protein heparanase 2 (HPA2) encoded by HPSE2 has been associated with numerous cancers [36][37][38][39]. Initial studies in the CSL did identify mRNA expression of HPSE2 in female lower genital tract tissue both in animals with UGC and those without, but did not find a difference according to disease state or between different Pv11 genotypes [11].…”

Heparanase Induces Signal Transducer and Activator of Transcription (STAT) Protein Phosphorylation

“…Immunostaining-Staining of formalin-fixed, paraffin-embedded 5-micron sections was performed essentially as described (17,32,33). Briefly, slides were deparaffinized and rehydrated, and endogenous peroxidase activity was quenched (30 min) by 3% hydrogen peroxide in methanol.…”

Urinary Tract Effects of HPSE2 Mutations

“…Most (i.e., nonsense or frameshift mutations) would cause loss of function, but a subset may generate abnormal proteins. In Family 2, the deleted amino acids in exon 3 correspond to the linker sequence in heparanase 1 cleaved to yield an active enzyme, [8][9][10][11] and an exon 3 deletion was previously reported in a Spanish child with UFS. 4 The in-frame deletion of asparagine 254 in Family 6 targets an amino acid conserved between human, mouse, and frog heparanase 2.…”

“…A sister with unilateral VUR carried one copy of the variant, an in-frame deletion of Asp141 with insertion of three residues, GluProGly ( Figure 1, B and C). The insertion lies between the equivalent sequence, which links the two heparanase 1 subunits, 8,9 and thus, by analogy, may functionally disrupt heparanase 2. Heterozygous missense variants with a minor allele frequency ,1% (Supplemental Table 1) were not over-represented in patients (5 of 439 probands) versus European ancestry controls (38 of 6503 cases; P=0.2).…”

“…Biallelic mutations of HPSE2 cause UFS. [4][5][6][7] HPSE2 encodes heparanase 2, 8 which inhibits endo-b-Dglucuronidase activity of heparanase 1, 9 itself implicated in releasing growth factors from heparan sulfate proteoglycans. [10][11][12] Since the first descriptions of HPSE2 mutations in UFS in 2010, 4,5 only two further such families have been reported.…”