Overexpression of elafin in ovarian carcinoma is driven by genomic gains and activation of the nuclear factor kappaB pathway and is associated with poor overall survival.

Ovarian cancer is a leading cause of cancer mortality in women. The aim of this study was to elucidate whether whey acidic protein (WAP) genes on chromosome 20q13.12, a region frequently amplified in this cancer, are expressed in serous carcinoma, the most common form of the disease. Herein, we report that a trio of WAP genes (HE4, SLPI, and Elafin) is overexpressed and secreted by serous ovarian carcinomas. To our knowledge, this is the first report linking Elafin to ovarian cancer. Fluorescence in situ hybridization analysis of primary tumors demonstrates genomic gains of the Elafin locus in a majority of cases. In addition, a combination of peptidomimetics, RNA interference, and chromatin immunoprecipitation experiments shows that Elafin expression can be transcriptionally upregulated by inflammatory cytokines through activation of the nuclear factor kappaB pathway. Importantly, using a clinically annotated tissue microarray composed of late-stage, high-grade serous ovarian carcinomas, we show that Elafin expression correlates with poor overall survival. These results, combined with our observation that Elafin is secreted by ovarian tumors and is minimally expressed in normal tissues, suggest that Elafin may serve as a determinant of poor survival in this disease.

[1]  M. Kiechle,et al.  Comparative genomic hybridization detects genetic imbalances in primary ovarian carcinomas as correlated with grade of differentiation , 2001, Cancer.

[2]  P. Meltzer,et al.  Frequent amplification of chromosomal region 20q12-q13 in ovarian cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  A. Kulkarni,et al.  Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing , 2000, Nature Medicine.

[4]  Daniela Taverna,et al.  Identification of new genes associated with breast cancer progression by gene expression analysis of predefined sets of neoplastic tissues , 2008, International journal of cancer.

[5]  H. Lilja,et al.  The evolution of a genetic locus encoding small serine proteinase inhibitors. , 2005, Biochemical and biophysical research communications.

[6]  D. Curiel,et al.  An immunomagnetic-based method for the purification of ovarian cancer cells from patient-derived ascites. , 2001, Gynecologic oncology.

[7]  A. Arakawa,et al.  Use of serum secretory leukocyte protease inhibitor levels in patients to improve specificity of ovarian cancer diagnosis. , 2005, Gynecologic oncology.

[8]  K. Ohlsson,et al.  The presence of elafin, SLPI, IL1-RA and STNFalpha RI in head and neck squamous cell carcinomas and their relation to the degree of tumour differentiation. , 2002, Mediators of inflammation.

[9]  Christopher P Crum,et al.  Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. , 2005, Cancer research.

[10]  J. Schröder,et al.  Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. , 1990, The Journal of biological chemistry.

[11]  Å. Lundwall,et al.  The gene of the protease inhibitor SKALP/elafin is a member of the REST gene family. , 1996, Biochemical and biophysical research communications.

[12]  P. M. Das,et al.  Chromatin immunoprecipitation assay. , 2004, BioTechniques.

[13]  E. Kohn,et al.  The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells. , 2007, Carcinogenesis.

[14]  José J. Cuenca,et al.  Cirugía coronaria sin circulación extracorpórea y otras técnicas mínimamente invasivas , 2005 .

[15]  L. Bingle,et al.  Cytokine-mediated induction of the human elafin gene in pulmonary epithelial cells is regulated by nuclear factor-kappaB. , 2001, American journal of respiratory cell and molecular biology.

[16]  S. Skates,et al.  Urokinase-Type Plasminogen Activator Receptor: A Beacon of Malignancy? , 2008, Clinical Cancer Research.

[17]  J. Sallenave,et al.  SLPI and elafin: one glove, many fingers. , 2006, Clinical science.

[18]  B. Stewart,et al.  World Cancer Report , 2003 .

[19]  José Cuenca,et al.  [Off-pump coronary artery bypass grafting and other minimally invasive techniques]. , 2005, Revista espanola de cardiologia.

[20]  R. Romero,et al.  Identification of novel functional sequence variants in the gene for peptidase inhibitor 3 , 2006, BMC Medical Genetics.

[21]  S. Ghosh,et al.  Shared Principles in NF-κB Signaling , 2008, Cell.

[22]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[23]  Pablo Tamayo,et al.  CDK8 is a colorectal cancer oncogene that regulates β-catenin activity , 2008, Nature.

[24]  Y. Kluger,et al.  Using a xenograft model of human breast cancer metastasis to find genes associated with clinically aggressive disease. , 2005, Cancer research.

[25]  Ralph S Freedman,et al.  Ovarian cancer, the coagulation pathway, and inflammation , 2005, Journal of Translational Medicine.

[26]  J. Schalkwijk,et al.  Differential expression of SKALP/Elafin in human epidermal tumors. , 1993, The American journal of pathology.

[27]  E. Friedman,et al.  In silico chromosomal clustering of genes displaying altered expression patterns in ovarian cancer. , 2005, Cancer genetics and cytogenetics.

[28]  Michèl Schummer,et al.  The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. , 2003, Cancer research.

[29]  D R Schwartz,et al.  Coordinately up-regulated genes in ovarian cancer. , 2001, Cancer research.

[30]  R. Ivell,et al.  A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. , 1991, Biology of reproduction.

[31]  K. Hunt,et al.  Differential regulation of elafin in normal and tumor-derived mammary epithelial cells is mediated by CCAAT/enhancer binding protein beta. , 2007, Cancer research.

[32]  R. Bast,et al.  Status of tumor markers in ovarian cancer screening. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  M. Ogawa,et al.  Immunohistochemical expression of SKALP/elafin in squamous cell carcinoma of human lung. , 2003, Oncology reports.

[34]  A. Clauss,et al.  Identification of a novel protease inhibitor gene that is highly expressed in the prostate. , 2002, Biochemical and biophysical research communications.

[35]  M. Jordana,et al.  Regulation of secretory leukocyte proteinase inhibitor (SLPI) and elastase-specific inhibitor (ESI/elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. , 1994, American journal of respiratory cell and molecular biology.

[36]  D. Pinkel,et al.  Genetic analysis of benign, low-grade, and high-grade ovarian tumors. , 1995, Cancer research.

[37]  M. Morgan,et al.  Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer. , 2000, Epidemiology.

[38]  N. Devoogdt,et al.  Secretory Leukocyte Protease Inhibitor in Cancer Development , 2004, Annals of the New York Academy of Sciences.

[39]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[40]  Y. Bourbonnais,et al.  Proteins with whey-acidic-protein motifs and cancer. , 2006, The Lancet. Oncology.

[41]  H. Egami,et al.  Immunohistochemical expression of SKALP/elafin in squamous cell carcinoma of the oesophagus. , 1997, British Journal of Cancer.

[42]  A. Godwin,et al.  Comparative genomic hybridization detects frequent overrepresentation of chromosomal material from 3q26, 8q24, and 20q13 in human ovarian carcinomas , 1997, Genes, chromosomes & cancer.

[43]  R. Ness,et al.  Possible role of ovarian epithelial inflammation in ovarian cancer. , 1999, Journal of the National Cancer Institute.

[44]  M. McKay,et al.  Cancer of the ovary. , 1994, The New England journal of medicine.

[45]  R. Sager,et al.  Differential expression of elafin in human normal mammary epithelial cells and carcinomas is regulated at the transcriptional level. , 1995, Cancer research.

[46]  V. Castronovo,et al.  Experimental anti‐angiogenesis causes upregulation of genes associated with poor survival in glioblastoma , 2007, International journal of cancer.

[47]  S. Ghosh,et al.  Characterization of the IκB-kinase NEMO Binding Domain* , 2002, The Journal of Biological Chemistry.

[48]  H. Lilja,et al.  A locus on human chromosome 20 contains several genes expressing protease inhibitor domains with homology to whey acidic protein. , 2002, The Biochemical journal.