Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines

Yoshitaka Sekido, Scott A. Bader, David P. Carbone, Bruce E. Johnson, John D. Minna

Research output: Contribution to journalArticle

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Abstract

Small cell lung cancer (SCLC) is known to express the HuD protein, the neuronal antigen homologous to Drosophila Elav and Sxl genes involved in neuronal and sex development. HuD is the target of an immune response including high titered antibodies causing paraneoplastic encephalomyelitis and sensory neuropathy. Because the p53 recessive oncogene is mutated and anti-p53 antibodies frequently occur in cancer patients, we wondered if the development of anti-HuD antibodies signaled the presence of HuD mutations in long cancer. The HuD gene was mapped to chromosome region 1p using a human- mouse hybrid cell panel. We confirmed that 26 of 46 cancer (43 lung cancer and 3 mesothelioma) cell lines expressed HuD mRNA and that this expression, as well as protein expression by Western blot, correlated strongly with the SCLC neuroendocrine phenotype. Southern blot and single-strand conformation polymorphism analyses showed that HuD was not mutated in 78 lung cancers, including patients with the severe paraneoplastic syndrome. Northern blot analysis showed that lung cancer cell lines expressed two major mRNAs (4.3 and 4.0 kilobases) of HuD. We found the three previously described alternative spliced mRNA forms (HuDpro, HuD, and HuDmex). In addition, we also found HuD mRNA had an alternative splicing form in its 5'-coding region. This alternative splice introduced 87 base pairs of sequence and a termination codon resulting in a predicted small, truncated protein (11 amino acids) reminiscent of the male-specific truncated protein in the Sex-lethal (Sxl) gene of Drosophila. However, mRNAs encoding both full-length and truncated proteins were expressed in all SCLCs. These results show that the HuD gene is not mutated in lung cancer, including tumors from patients producing anti-HuD antibodies, but HuD expression is an independent marker or determinant of the neuroendocrine differentiation seen in SCLC.

Original languageEnglish (US)
Pages (from-to)4988-4992
Number of pages5
JournalCancer Research
Volume54
Issue number18
StatePublished - Sep 15 1994

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Nervous System Paraneoplastic Syndromes
Lung Neoplasms
Small Cell Lung Carcinoma
Antigens
Cell Line
Messenger RNA
Lethal Genes
Anti-Idiotypic Antibodies
Genes
Drosophila
Proteins
Paraneoplastic Syndromes
Neoplasms
Sexual Development
Terminator Codon
Hybrid Cells
Mesothelioma
Alternative Splicing
Southern Blotting
Tumor Suppressor Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines. / Sekido, Yoshitaka; Bader, Scott A.; Carbone, David P.; Johnson, Bruce E.; Minna, John D.

In: Cancer Research, Vol. 54, No. 18, 15.09.1994, p. 4988-4992.

Research output: Contribution to journalArticle

Sekido, Yoshitaka ; Bader, Scott A. ; Carbone, David P. ; Johnson, Bruce E. ; Minna, John D. / Molecular analysis of the HuD gene encoding a paraneoplastic encephalomyelitis antigen in human lung cancer cell lines. In: Cancer Research. 1994 ; Vol. 54, No. 18. pp. 4988-4992.
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abstract = "Small cell lung cancer (SCLC) is known to express the HuD protein, the neuronal antigen homologous to Drosophila Elav and Sxl genes involved in neuronal and sex development. HuD is the target of an immune response including high titered antibodies causing paraneoplastic encephalomyelitis and sensory neuropathy. Because the p53 recessive oncogene is mutated and anti-p53 antibodies frequently occur in cancer patients, we wondered if the development of anti-HuD antibodies signaled the presence of HuD mutations in long cancer. The HuD gene was mapped to chromosome region 1p using a human- mouse hybrid cell panel. We confirmed that 26 of 46 cancer (43 lung cancer and 3 mesothelioma) cell lines expressed HuD mRNA and that this expression, as well as protein expression by Western blot, correlated strongly with the SCLC neuroendocrine phenotype. Southern blot and single-strand conformation polymorphism analyses showed that HuD was not mutated in 78 lung cancers, including patients with the severe paraneoplastic syndrome. Northern blot analysis showed that lung cancer cell lines expressed two major mRNAs (4.3 and 4.0 kilobases) of HuD. We found the three previously described alternative spliced mRNA forms (HuDpro, HuD, and HuDmex). In addition, we also found HuD mRNA had an alternative splicing form in its 5'-coding region. This alternative splice introduced 87 base pairs of sequence and a termination codon resulting in a predicted small, truncated protein (11 amino acids) reminiscent of the male-specific truncated protein in the Sex-lethal (Sxl) gene of Drosophila. However, mRNAs encoding both full-length and truncated proteins were expressed in all SCLCs. These results show that the HuD gene is not mutated in lung cancer, including tumors from patients producing anti-HuD antibodies, but HuD expression is an independent marker or determinant of the neuroendocrine differentiation seen in SCLC.",
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