Human hyaluronidases map to a candidate tumor suppressor locus

Eukaryotic hyaluronidases are widely distributed, but until recently the only vertebrate enzyme to be cloned was the sperm-specific enzyme, PH20. We have now purified the hyaluronidase of human plasma The identical enzyme, as well as a second proteolytically processed form, is present in urine. Amino acid sequence of the purified hyaluronidase matched a cDNA in the human Expressed Sequence Tag database which, in combination with 5'-RACE-PCR, was used to clone the gene, termed HYAL1, coding for a protein of 435 amino acids. HYAL1 is identical to an uncharacterized gene positionally cloned by others at chromosome 3p21.3 that is homozygously deleted in several small cell lung carcinoma cell lines. We have also identified two additional paralogous hyaluronidase-like genes flanking HYAL1 on chromosome 3p21.3 termed HYAL2 and HYAL3. We are evaluating the candidacy of these two genes as potential tumor suppressors. The mouse hyaluronidase gene, by convention termed Hyal1, was also cloned and expressed and found to be 73% identical to the human enzyme. In mouse, serum hyaluronidase polymorphism has previously been mapped to 60 cM from the centromere of chromosome 9, which corresponds to a cytogenetic location of 9F1-F2, a region syntenic to the human 3p21.3. Mice with alleles of Hyal1 producing higher levels of plasma hyaluronidase have greater resistance to transplanted tumor growth. Products of these candidate tumor suppressor genes are being evaluated as potential anticancer agents.