title: Alternatively spliced Spalax heparanase inhibits extracellular matrix degradation, tumor growth, and metastasis.
abstract: Heparanase is an endoglycosidase that degrades heparan sulfate (HS) at the cell surface and in the extracellular matrix. Heparanase is expressed mainly by cancer cells, and its expression is correlated with increased tumor aggressiveness, metastasis, and angiogenesis. Here, we report the cloning of a unique splice variant (splice 36) of heparanase from the subterranean blind mole rat (Spalax). This splice variant results from skipping part of exon 3, exons 4 and 5, and part of exon 6 and functions as a dominant negative to the wild-type enzyme. It inhibits HS degradation, suppresses glioma tumor growth, and decreases experimental B16-BL6 lung colonization in a mouse model. Intriguingly, Spalax splice variant 7 of heparanase (which results from skipping of exon 7) is devoid of enzymatic activity, but unlike splice 36 it enhances tumor growth. Our results demonstrate that alternative splicing of heparanase regulates its enzymatic activity and might adapt the heparanase function to the fluctuating normoxic-hypoxic subterranean environment that Spalax experiences. Development of anticancer drugs designed to suppress tumor growth, angiogenesis, and metastasis is a major challenge, of which heparanase inhibition is a promising approach. We anticipate that the heparanase splicing model, evolved during 40 million years of Spalacid adaptation to underground life, would pave the way for the development of heparanase-based therapeutic modalities directed against angiogenesis, tumor growth, and metastasis.
authors.affiliation: Department of Oncology, Shaare Zedek Medical Center, Jerusalem 91031, Israel.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Nasser
authors.forename: Aaron
authors.initials: A
authors.lastname: Avivi
authors.forename: Itay
authors.initials: I
authors.lastname: Shafat
authors.forename: Evgeny
authors.initials: E
authors.lastname: Edovitsky
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Eviatar
authors.initials: E
authors.lastname: Nevo
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D005109:Extracellular Matrix / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D051381:Rats; D046308:Spalax; D000099175:Heparanase
chemical_list: D000970:Antineoplastic Agents; D005966:Glucuronidase; D006026:Glycoside Hydrolases; D000099175:Heparanase