Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster.

Fas-mediated apoptosis is an important regulator of cell survival, and abnormalities in this system have been shown to result in a number of human pathological conditions. A secreted member of the tumor necrosis factor receptor superfamily, DcR3, was recently reported to be amplified in human lung and colon cancers as a negative regulator of Fas-mediated apoptosis. We identified this gene, which we call M68. M68 genomic DNA, mRNA, and protein levels were examined in a series of human gastrointestinal tract tumors. Using M68 immunohistochemistry and a scoring system similar to that used for HER-2/neu, we found that M68 protein was overexpressed in 30 of 68 (44%) human adenocarcinomas of the esophagus, stomach, colon, and rectum. Tumors examined by Northern blot revealed M68 mRNA highly elevated in a similar fraction of primary tumors from the same gastrointestinal tract regions, as well as in the colon adenocarcinoma cell lines SW480 and SW1116. Further, we found M68 protein to be overexpressed in a substantial number of tumors in which gene amplification could not be detected by fluorescence in situ hybridization or quantitative genomic PCR, suggesting that overexpression of M68 may precede amplification in tumors. Finally, we find that M68 lies within a four-gene cluster that includes a novel helicase-like gene (NHL) related to RAD3/ERCC2, a plasma membrane Ras-related GTPase and a member of the stathmin family, amplification or overexpression of which may also contribute to cell growth and tumor progression.

[1]  M. Metzker,et al.  Identification of the gene responsible for Best macular dystrophy , 1998, Nature Genetics.

[2]  P. Galle,et al.  Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1 /Fas) Mediated apoptosis , 1998, Nature Medicine.

[3]  J. Inazawa,et al.  Comparative genomic hybridization of squamous cell carcinoma of the esophagus: The possible involvement of the DP1 gene in the 13q34 amplicon , 1999, Genes, chromosomes & cancer.

[4]  T. Fleisher,et al.  The role of Fas and related death receptors in autoimmune and other disease states. , 1999, The Journal of allergy and clinical immunology.

[5]  J. Wisecarver.  HER-2/neu testing comes of age. , 1999, American journal of clinical pathology.

[6]  I. Petersen,et al.  Chromosome alterations in breast carcinomas: frequent involvement of DNA losses including chromosomes 4q and 21q. , 1998, British Journal of Cancer.

[7]  T Takahashi,et al.  Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization , 1999, Genes, chromosomes & cancer.

[8]  L. Thompson,et al.  ERCC2: cDNA cloning and molecular characterization of a human nucleotide excision repair gene with high homology to yeast RAD3. , 1990, The EMBO journal.

[9]  D. Botstein,et al.  Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer , 1998, Nature.

[10]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[11]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[12]  K. Mafune,et al.  Coexpression of Grb7 with epidermal growth factor receptor or Her2/erbB2 in human advanced esophageal carcinoma. , 1997, Cancer research.

[13]  R. Myers,et al.  Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes. , 1990, Science.

[14]  I. Bièche,et al.  Overexpression of the stathmin gene in a subset of human breast cancer. , 1998, British Journal of Cancer.

[15]  Jian Ni,et al.  A Newly Identified Member of Tumor Necrosis Factor Receptor Superfamily (TR6) Suppresses LIGHT-mediated Apoptosis* , 1999, The Journal of Biological Chemistry.

[16]  L. Naumovski,et al.  RAD3 gene of Saccharomyces cerevisiae: nucleotide sequence of wild-type and mutant alleles, transcript mapping, and aspects of gene regulation , 1985, Molecular and cellular biology.

[17]  Y. Yazaki,et al.  Isolation of a candidate gene, CAB1, for cholesterol transport to mitochondria from the c-ERBB-2 amplicon by a modified cDNA selection method. , 1997, Cancer research.

[18]  S. Nagata,et al.  Essential roles of the Fas ligand in the development of hepatitis , 1997, Nature Medicine.

[19]  P. Hall,et al.  Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. , 1994, Journal of cell science.

[20]  R Akita,et al.  Her-2/neu expression in node-negative breast cancer: direct tissue quantitation by computerized image analysis and association of overexpression with increased risk of recurrent disease. , 1993, Cancer research.

[21]  L. Prakash,et al.  The nucleotide sequence of the RAD3 gene of Saccharomyces cerevisiae: a potential adenine nucleotide binding amino acid sequence and a nonessential acidic carboxyl terminal region. , 1985, Nucleic acids research.

[22]  Jacques Ferlay,et al.  Estimates of the worldwide incidence of 25 major cancers in 1990 , 1999, International journal of cancer.

[23]  Daniel S. Miller,et al.  Annual report to the nation on the status of cancer, 1973-1996, with a special section on lung cancer and tobacco smoking. , 1999, Journal of the National Cancer Institute.

[24]  V. Dixit,et al.  Apoptosis control by death and decoy receptors. , 1999, Current opinion in cell biology.

[25]  A. Sobel,et al.  SCLIP: A Novel SCG10‐Like Protein of the Stathmin Family Expressed in the Nervous System , 1998, Journal of neurochemistry.

[26]  A. Look,et al.  Novel regions of chromosomal loss in familial neuroblastoma by comparative genomic hybridization , 1997, Genes, chromosomes & cancer.

[27]  H. Mueller.  Tumor necrosis factor as an antineoplastic agent: pitfalls and promises , 1998, Cellular and Molecular Life Sciences CMLS.

[28]  J. W. Wilson,et al.  Regulation and Significance of Apoptosis in the Stem Cells of the Gastrointestinal Epithelium , 1997, Stem cells.

[29]  H. Ball,et al.  Overlapping gene structure of the human neuropeptide Y receptor subtypes Y1 and Y5 suggests coordinate transcriptional regulation. , 1997, Genomics.

[30]  B. Dutrillaux,et al.  Identification of amplified DNA sequences in breast cancer and their organization within homogeneously staining regions , 1995, Genes, chromosomes & cancer.

[31]  D. Green.  Apoptosis: Death deceiver , 1998, Nature.

[32]  D. Ferrari,et al.  Apoptosis signaling by death receptors. , 1998, European journal of biochemistry.

[33]  Terry Farrah,et al.  The TNF receptor superfamily of cellular and viral proteins: Activation, costimulation, and death , 1994, Cell.

[34]  A. Schürmann,et al.  ARP Is a Plasma Membrane-associated Ras-related GTPase with Remote Similarity to the Family of ADP-ribosylation Factors (*) , 1995, The Journal of Biological Chemistry.

[35]  D. Slamon,et al.  HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  E. Reddy,et al.  Transducers of life and death: TNF receptor superfamily and associated proteins. , 1996, Oncogene.