Human hyaluronidases map to a candidate tumor suppressor locus

Trends In Collagen


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 Hyall, 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 Hyall 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.


Hyaluronidase chromosome 3p21.3 tumor suppressors 


  1. 1.
    Kreil G 1995Protein Sci. 4 1666Google Scholar
  2. 2.
    Frost G I, Csoka T and Stern R 1996Trends in Glycosci. Glycotechnol. 8 419Google Scholar
  3. 3.
    Afify A M, Stern M, Guntenhoner M and Stern R 1993Arch. Biochem. Biophys. 305 434CrossRefGoogle Scholar
  4. 4.
    Frost G I, Csóka T B, Wong T and Stern R 1997Biochem. Biophys. Res. Commun. 236 10CrossRefGoogle Scholar
  5. 5.
    Csóka T B, Frost G I, Wong T and Stern R 1997FEBS Lett. 417 307CrossRefGoogle Scholar
  6. 6.
    Csóka T B, Frost G I, Heng H H Q, Scherer S W, Mohapatra G and Stern R 1998Genomics 48 63CrossRefGoogle Scholar
  7. 7.
    De Maeyer E and De Maeyer-Guignard J 1992Int. J. Cancer 51 657CrossRefGoogle Scholar
  8. 8.
    Pawlowski A, Haberman H F and Menon I A 1979Int. J. Cancer 23 105CrossRefGoogle Scholar
  9. 9.
    Hosoe S, Shigedo Y, Ueno K, Tachibana I, Osaki T, Tanio Y, Kawase I, Yamakawa K, Nakamura Y and Kishimoto T 1994Lung Cancer 10 297CrossRefGoogle Scholar
  10. 10.
    Mitsudomi T, Oyama T, Nishida K, Ogami A, Osaki T, Sugio K, Yasumoto K, Sugimachi K and Gazdar A 1996Clin. Cancer Res. 2 1185Google Scholar
  11. 11.
    Todd S, Franklin W A, Varella-Garcia M, Kennedy T, Hilliker C E, Jr, Hahner L, Anderson M, Wiest J S, Drabkin H A and Gemmill R M 1997Cancer Res. 57 1344Google Scholar
  12. 12.
    Kovatich A, Friedland D M, Druck T, Hadaczek P, Huebner K, Comis R L, Hauck W and McCue P A 1998Cancer 83 1109CrossRefGoogle Scholar
  13. 13.
    Weigel P H, Hascall V C and Tammi M 1997J. Biol. Chem. 272 13997CrossRefGoogle Scholar
  14. 14.
    Prehm P 1984Biochem. J. 220 597Google Scholar
  15. 15.
    Toole B P 1991 InCell biology of the extracellular matrix (ed.) E Hay (New York: Plenum), pp 305–341Google Scholar
  16. 16.
    Laurent T C and Fraser J R 1992FASEB J. 6 2397Google Scholar
  17. 17.
    Turley E A 1992Cancer Metastasis Rev. 11 21CrossRefGoogle Scholar
  18. 18.
    Underhill C B 1992J. Cell Sci. 103 293Google Scholar
  19. 19.
    Naor D, Sionov R V and Ish-Shalom D 1997Adv. Cancer Res. 71 241CrossRefGoogle Scholar
  20. 20.
    Lesley J and Hyman R 1998Front Biosci. 3 616Google Scholar
  21. 21.
    Hall C L and Turley E A 1995J. Neurooncol. 26 221CrossRefGoogle Scholar
  22. 22.
    Entwistle J, Hall C L and Turley E A 1996J. Cell Biochem. 61 569CrossRefGoogle Scholar
  23. 23.
    Toole B P 1990Curr. Opin. Chem. Biol. 2 839Google Scholar
  24. 24.
    Knudson C B and Knudson W 1993FASEB J. 7 1233Google Scholar
  25. 25.
    Wight T, Heingard D and Hascall V 1991 InCell biology of extracellular matrix. (ed.) E Hay (New York: Plenum Press) pp. 45–78Google Scholar
  26. 26.
    Zhao M, Yoneda M, Ohashi Y, Kurono S, Iwata H, Ohnuki Y and Kimata K 1995J. Biol. Chem. 270 26657CrossRefGoogle Scholar
  27. 27.
    Knudson W 1996Am. J. Pathol. 148 1721Google Scholar
  28. 28.
    Zhang L, Underhill C B and Chen L 1995Cancer Res. 55 428Google Scholar
  29. 29.
    De Salegui M and Pigman W 1967Arch. Biochem. Biophys. 120 60CrossRefGoogle Scholar
  30. 30.
    Fenger M 1982J. Chromatogr. 240 173CrossRefGoogle Scholar
  31. 31.
    Zhu L, Hope T J, Hall J, Davies A, Stern M, Muller-Ebernard U, Stern R and Parslow T G 1994J. Biol. Chem. 269 32092Google Scholar
  32. 32.
    Hrkal Z, Kuzelová K, Muller-Eberhard U and Stern R 1996FEBS Lett. 383 72CrossRefGoogle Scholar
  33. 33.
    Nadeau J H 1986Genet. Res. 48 175CrossRefGoogle Scholar
  34. 34.
    Imai K 1997Mammalian Genome 7 S159Google Scholar
  35. 35.
    Lepperdinger G, Strobl B and Kreil G 1998J. Biol. Chem. 273 22466CrossRefGoogle Scholar
  36. 36.
    Berlyne G M 1960Clin. Sci. 19 619Google Scholar
  37. 37.
    Cobbin L B and Dicker S E 1962J. Physiol. 163 168Google Scholar
  38. 38.
    Dicker S E and Franklin C S 1966J. Physiol. 186 110Google Scholar
  39. 39.
    Fiszer-Szafarz B 1984Anal. Biochem. 143 76CrossRefGoogle Scholar
  40. 40.
    Cherr G N, Meyers S A, Yudin A I, VandeVoort C A, Myles D G, Primakoff P and Overstreet J W 1996Dev. Biol. 175 142CrossRefGoogle Scholar
  41. 41.
    Hunnicutt G R, Mahan K, Lathrop W F, Ramarao C S, Myles D G and Primakoff P 1996Biol. Reprod. 54 1343CrossRefGoogle Scholar
  42. 42.
    Renkema G H, Boot R G, Strijland A, Donker-Koopman W E, van den Berg M, Muijsers A O and Aerts J M 1997Euro. J. Biochem. 244 279CrossRefGoogle Scholar
  43. 43.
    Fiszer-Szafarz B and De Maeyer E 1989Somatic Cell Mol. Genet. 15 79CrossRefGoogle Scholar
  44. 44.
    De Maeyer-Guignard J, Cachard-Thomas A and De Maeyer E 1991J. Exp. Zool. 258 246CrossRefGoogle Scholar
  45. 45.
    McBride W H and Bard J B 1979J. Exp. Med. 149 507CrossRefGoogle Scholar
  46. 46.
    Dick S J, Macchi B, Papazoglou S, Oldfield E H, Kornblith P L, Smith B H and Gately M K 1983Science 220 739CrossRefGoogle Scholar
  47. 47.
    Knudson W, Biswas C, Li X Q, Nemec R E and Toole B P 1989Ciba Found. Symp. 413 150; discussion pp 159–69, 281–5Google Scholar
  48. 48.
    Ozzello L, Lasfargues E and Murray M 1960Cancer Res. 20 600Google Scholar
  49. 49.
    Toole B P, Biswas C and Gross J 1979Proc. Natl. Acad. Sci. USA 76 6299CrossRefGoogle Scholar
  50. 50.
    Fiszer-Szafarz B and Gullino P M 1970Proc. Soc. Exp. Biol. Med. 133 805Google Scholar
  51. 51.
    Fiszer-Szafarz B and Szafarz D 1973Cancer Res. 33 1104Google Scholar
  52. 52.
    Wilkinson C R, Bower L M and Warren C 1996Clin. Chim. Acta 256 165CrossRefGoogle Scholar
  53. 53.
    Wei M H, Latif F, Bader S, Kashuba V, Chen J Y, Duh F M, Sekido Y, Lee C C, Geil L, Kuzmin I, Zabarovsky E, Klein G, Zbar B, Minna J D and Lerman M I 1986Cancer Res. 56 1487Google Scholar
  54. 54.
    Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y, Ariyoshi Y, Suyama M, Takagi H and Nakamura Y 1992Oncogene 7 445Google Scholar
  55. 55.
    Wu C L, Sloan P, Read A P, Harris R and Thakker N 1994Cancer Res. 54 6484Google Scholar
  56. 56.
    Hung J, Kishimoto Y, Sugio K, Virmani A, McIntire D D, Minna J D and Gazdar A F 1995J. Am. Med. Assoc. 273 1908CrossRefGoogle Scholar
  57. 57.
    Yokoyama S, Yamakawa K, Tsuchiya E, Murata M, Sakiyama S and Nakamura Y 1992Cancer Res. 52 873Google Scholar
  58. 58.
    Daly M C, Xiang R H, Buchhagen D, Hensel C H, Garcia D K, Killary A M, Minna J D and Naylor S L 1993Oncogene 8 1721Google Scholar
  59. 59.
    Lu Y Y, Jhanwar S C, Cheng J Q and Testa J R 1994Genes, Chromosomes Cancer 9 76CrossRefGoogle Scholar
  60. 60.
    Craighead J E and Mossman B T 1982N. Engl. J. Med. 306 1446Google Scholar
  61. 61.
    Cheng Y, Poulos N, Lung M, Hampton G, Ou B, Lerman M and Stanbridge E 1998Proc. Natl. Acad. Sci. USA 95 3042CrossRefGoogle Scholar
  62. 62.
    Huang D P, Ho J H, Chan W K, Lau W H and Lui M 1989Int. J. Cancer 43 936CrossRefGoogle Scholar
  63. 63.
    Latif F, Duh F M, Bader S, Sekido Y, Li H, Geil L, Zbar B, Minna J D and Lerman M I 1997Hum. Genet. 99 334CrossRefGoogle Scholar
  64. 64.
    Sekido Y, Ahmadian M, Wistuba II, Latif F, Bader S, Wei M H, Duh F M, Gazdar A F, Lerman M I and Minna J D 1998Oncogene 16 3151CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 1999

Authors and Affiliations

  1. 1.Department of GerontologyUniversity Medical School of DebrecenHungary
  2. 2.Department of PathologyUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations