Abstract
The hyaluronidase first isolated from human plasma, Hyal-1, is expressed in many somatic tissues. The Hyal-1 gene, HYAL1, also known as LUCA-1, maps to chromosome 3p21.3 within a candidate tumor suppressor gene locus defined by homozygous deletions and by functional tumor suppressor activity. Hemizygosity in this region occurs in many malignancies, including squamous cell carcinomas of the head and neck. We have investigated whether cell lines derived from such malignancies expressed Hyal-1 activity, using normal human keratinocytes as controls. Hyal-1 enzyme activity and protein were absent or markedly reduced in six of seven carcinoma cell lines examined. Comparative genomic and fluorescence in situ hybridization identified chromosomal deletions of one allele of HYAL1 in six of seven cell lines. Initial RT–PCR analyses demonstrated marked discrepancies between levels of HYAL1 mRNA and protein. Despite repeated sequence analyses, no mutations were found. However, two species of transcripts were identified when primers were used that included the 5′ untranslated region. The predominant mRNA species did not correlate with protein translation and contained a retained intron. A second spliced form lacking this intron was found only in cell lines that produced Hyal-1 protein. Inactivation of HYAL1 in these tumor lines is a result of incomplete splicing of its pre-mRNA that appears to be epigenetic in nature.
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References
Baylin SB, Herman JG, Graff JR, Vertino PM and Issa JP. . 1998 Adv. Cancer Res. 72: 141–196.
Buchhagen DL, Worsham MJ, Dyke DL and Carey TE. . 1996 Head Neck 18: 529–537.
Cheng Y, Poulos NE, Lung ML, Hampton G, Ou B, Lerman MI and Stanbridge EJ. . 1998 Proc. Natl. Acad. Sci. USA 95: 3042–3047.
Csóka TB, Frost GI, Wong T and Stern R. . 1997a FEBS Lett. 417: 307–310.
Csóka TB, Frost GI, Heng HH, Scherer SW, Mohapatra G and Stern R. . 1998 Genomics 48: 63–70.
Csóka AB, Scherer SW and Stern R. . 1999 Genomics 60: 356–361.
Csóka TB, Frost GI, Wong T and Stern R. . 1997b FEBS Lett. 417: 307–310.
Druck T, Berk L and Huebner K. . 1998 Oncol. Res. 10: 341–345.
Frost GI and Stern R. . 1997 Anal. Biochem. 251: 263–269.
Frost GI, Csóka TB and Stern R. . 1996 Trends Glycosci. Glycotech. 8: 419–434.
Frost GI, Csóka TB, Wong T and Stern R. . 1997 Biochem. Biophys. Res. Commun. 236: 10–15.
Gayther SA, Barski P, Batley SJ, Li L, de Foy KA, Cohen SN, Ponder BA and Caldas C. . 1997 Oncogene 15: 2119–2126.
Gmachl M, Sagan S, Ketter S and Kreil G. . 1993 FEBS Lett. 336: 545–548.
Granadino B, Penalva LOF, Green MR, Valcarcel J and Sanchez L. . 1997 Proc. Natl. Acad. Sci. USA 94: 7343–7348.
Guntenhoener MW, Pogrel MA and Stern R. . 1992 Matrix 12: 388–396.
Haber D and Harlow E. . 1997 Nat. Genet. 16: 320–322.
Heckel D, Comtesse N, Brass N, Blin N, Zang KD and Meese E. . 1998 Hum. Mol. Genet. 7: 1859–1872.
Hibi K, Takahashi T, Yamakawa K, Ueda R, Sekido Y, Ariyoshi Y, Suyama M, Takagi H, Nakamura Y and Takahashi T. . 1992 Oncogene 7: 445–449.
Knudson Jr AG. . 1971 Proc. Natl. Acad. Sci. USA 68: 820–823.
Kozak M. . 1991 J. Cell. Biol. 115: 887–903.
Kozak M. . 1996 Mamm. Genome 8: 563–574.
Kreil G. . 1995 Protein Sci. 4: 1666–1669.
Latif F, Duh FM, Bader S, Sekido Y, Li H, Geil L, Zbar B, Minna JD and Lerman MI. . 1997 Hum. Genet. 99: 334–341.
Lepperdinger G, Strobl B and Kreil G. . 1998 J. Biol. Chem. 273: 22466–22470.
Maquat LE. . 1996 Am. J. Hum. Genet. 59: 279–286.
Mohapatra G, Kim DH and Feuerstein BG. . 1995 Genes Chromosomes Cancer 13: 86–93.
Mohapatra G, Moore DH, Kim DH, Grewal L, Hyun WC, Waldman FM, Pinkel D and Feuerstein BG. . 1997 Genes Chromosomes Cancer 20: 311–319.
Sager R. . 1997 Proc. Natl. Acad. Sci. USA 94: 952–955.
Scaloni A, Jones W, Pospischil M, Sassa S, Schneewind O, Popowicz AM, Bossa F, Graziano SL and Manning JM. . 1992 J. Lab. Clin. Med. 120: 546–552.
Sekido Y, Ahmadian M, Wistuba II, Latif F, Bader S, Wei MH, Duh FM, Gazdar AF, Lerman MI and Minna JD. . 1998 Oncogene 16: 3151–3157.
Todd S, Franklin WA, Varella-Garcia M, Kennedy T, Hilliker Jr CE, Hahner Anderson M, Wiest JS, Drabkin HA and Gemmill RM. . 1997 Cancer Res. 57: 1344–1352.
Wei MH, Latif F, Bader S, Kashuba V, Chen JY, Duh FM, Sekido Y, Lee CC, Geil L, Kuzmin I, Zabarovsky E, Klein G, Zbar B, Minna JD and Lerman MI. . 1996 Cancer Res. 56: 1487–1492.
Zhang J, Sun X, Qian Y, LaDuca JP and Maquat LE. . 1998 Mol. Cell. Biol. 18: 5272–5283.
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This work was supported by NIH grant P50 DE/CA11912 to R Stern and NIH T32DE07204 to GI Frost.
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Frost, G., Mohapatra, G., Wong, T. et al. HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA. Oncogene 19, 870–877 (2000). https://doi.org/10.1038/sj.onc.1203317
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DOI: https://doi.org/10.1038/sj.onc.1203317
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