355 MOLECULAR MECHANISMS OF DEFB1: A NEW TUMOR SUPPRESSOR GENE IN RENAL AND PROSTATE CANCERS

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2010355 MOLECULAR MECHANISMS OF DEFB1: A NEW TUMOR SUPPRESSOR GENE IN RENAL AND PROSTATE CANCERS Carrie Sun, Rebecca Arnold, Fray Marshall, Julia Dorin, and John Petros Carrie SunCarrie Sun Atlanta, GA More articles by this author , Rebecca ArnoldRebecca Arnold Atlanta, GA More articles by this author , Fray MarshallFray Marshall Atlanta, GA More articles by this author , Julia DorinJulia Dorin Edinburgh, United Kingdom More articles by this author , and John PetrosJohn Petros Atlanta, GA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.422AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Human beta defensin-1 (DEFB1) is a new candidate tumor suppressor gene located at chromosome 8p23 and is frequently deleted in both renal and prostate cancers. There are specific promoter polymorphisms that cause decreased gene expression and there is loss of the protein product in clinical specimens in 83% of prostate and 90% of renal cancers (Lab Invest 83:501; 2003). Conversely, overexpression induces apoptosis of malignant cells (Cancer Res 66:8543; 2006.) Because of the lack of appropriate laboratory models the mechanisms of action of this tumor suppressor have been poorly studied. The objectives of this study were therefore to generate an appropriate model system in which to study the molecular consequences of DEFB1 expression and discover the cell signaling pathways relevant to the action of DEFB1 in malignant cells. METHODS Using DEFB1 null mice (Infect Immun 70:3053; 2002) we generated immortalized renal epithelial cells by transfection with large T antigen and H-Ras V12. DEFB1 was re-introduced into these cells by retroviral transfection and the DEFB1 null and wild type cells compared for growth characteristics and cell signaling pathways by RT-PCR and western analysis. RESULTS Immortalized DEFB1 null renal epithelial cells grew well in vitro and as in vivo tumor xenografts in nude mice while the reintroduction of DEFB1 resulted in poor growth, and caused cell death in culture. DEFB1 knock-out cells exhibited up regulation of HER-2/neu receptor and phospho-ERK and reintroduction of DEFB1 reversed both of these molecular alterations. CONCLUSIONS We have developed an animal model system that closely resembles the clinical finding in renal cell carcinoma of the cancer-specific loss of DEFB1 expression in malignant renal epithelial cells. The molecular consequences of the loss of the tumor suppressor DEFB1 include upregulation of the HER-2/neu receptor and increased phosphorylation of ERG to the active form. This model system will allow future mechanistic evaluation of DEFB1 as a tumor suppressor and may be used to test novel molecular targeted therapies. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e141 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Carrie Sun Atlanta, GA More articles by this author Rebecca Arnold Atlanta, GA More articles by this author Fray Marshall Atlanta, GA More articles by this author Julia Dorin Edinburgh, United Kingdom More articles by this author John Petros Atlanta, GA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...