HYAL1(LUCA-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

Gregory I. Frost, Gayatry Mohapatra, Tim M. Wong, Antonei Benjamin Csóka, Joe Gray, Robert Stern

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)870-877
Number of pages8
JournalOncogene
Volume19
Issue number7
StatePublished - Feb 17 2000
Externally publishedYes

Fingerprint

RNA Precursors
Tumor Suppressor Genes
Chromosomes
Cell Line
Introns
Neoplasms
Messenger RNA
Proteins
Hyaluronoglucosaminidase
5' Untranslated Regions
Protein Biosynthesis
Fluorescence In Situ Hybridization
Keratinocytes
Epigenomics
Sequence Analysis
Alleles
Carcinoma
Polymerase Chain Reaction
Mutation
Carcinoma, squamous cell of head and neck

Keywords

  • 3p21.3
  • Aberrant splicing
  • Head and neck tumors
  • Hyaluronidase
  • Squamous cell carcinoma
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

HYAL1(LUCA-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. / Frost, Gregory I.; Mohapatra, Gayatry; Wong, Tim M.; Csóka, Antonei Benjamin; Gray, Joe; Stern, Robert.

In: Oncogene, Vol. 19, No. 7, 17.02.2000, p. 870-877.

Research output: Contribution to journalArticle

Frost, Gregory I. ; Mohapatra, Gayatry ; Wong, Tim M. ; Csóka, Antonei Benjamin ; Gray, Joe ; Stern, Robert. / HYAL1(LUCA-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. In: Oncogene. 2000 ; Vol. 19, No. 7. pp. 870-877.
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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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