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.
Clauss
Adam
A
Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA 02115, USA.
Ng
Vivian
V
Liu
Joyce
J
Piao
Huiying
H
Russo
Moises
M
Vena
Natalie
N
Sheng
Qing
Q
Hirsch
Michelle S
MS
Bonome
Tomas
T
Matulonis
Ursula
U
Ligon
Azra H
AH
Birrer
Michael J
MJ
Drapkin
Ronny
R
D014408:Biomarkers, Tumor / Q000032:analysis*; D015152:Blotting, Northern; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D053492:Elafin / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D016019:Survival Analysis; D046888:Tissue Array Analysis
D014408:Biomarkers, Tumor; D053492:Elafin; D016328:NF-kappa B; C506806:PI3 protein, human