358 EPIGENETIC UPREGULATION OF SECRETED FRIZZLED-RELATED PROTEIN 1 IN METASTATIC RENAL CELL CARCINOMAS: IMPLICATIONS ON INVASION AND METASTASIS

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2010358 EPIGENETIC UPREGULATION OF SECRETED FRIZZLED-RELATED PROTEIN 1 IN METASTATIC RENAL CELL CARCINOMAS: IMPLICATIONS ON INVASION AND METASTASIS Sharanjot Saini, Jan Liu, Shahana Majid, Soichiro Yamamura, Kazumori Kawakami, Hiroshi Hirata, Yuichiro Tanaka, Peter R. Carroll, and Rajvir Dahiya Sharanjot SainiSharanjot Saini More articles by this author , Jan LiuJan Liu More articles by this author , Shahana MajidShahana Majid More articles by this author , Soichiro YamamuraSoichiro Yamamura More articles by this author , Kazumori KawakamiKazumori Kawakami More articles by this author , Hiroshi HirataHiroshi Hirata More articles by this author , Yuichiro TanakaYuichiro Tanaka More articles by this author , Peter R. CarrollPeter R. Carroll More articles by this author , and Rajvir DahiyaRajvir Dahiya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.425AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Dysregulation of Wingless-type (Wnt) signaling pathway is common in a variety of human malignancies. Secreted Frizzled related proteins (SFRPs) are a family of secreted glycoproteins that act as modulators of Wnt signaling. The Secreted frizzled related protein 1 (SFRP1) is a Wnt antagonist that has been associated with various malignancies, including renal cell carcinomas (RCC). However, the functional significance of SFRP1 has never been investigated in metastatic RCC. Here we investigated the role of this molecule in kidney cancer progression and metastasis. METHODS RNA was extracted from a normal renal cell line (HK-2), primary RCC (A498, Caki2) and metastatic RCC cell lines (Caki1, ACHN and Hs891.T) and Wnt pathway-focused cDNA expression profiling was done to identify dysregulated components of Wnt signaling. SFRP1 expression was confirmed by quantitative real-time PCR and immunostaining in renal tissues. We explored the molecular mechanisms underlying SFRP1 upregulation by analyzing DNA methylation and histone modification patterns on SFRP1 promoter by bisulfite sequencing and Chromatin immunoprecipitation (ChIP) assay, respectively. Further, to understand the functional significance of SFRP1 overexpression in metastatic RCC with regard to tumorigenesis, we used siRNA-mediated approach to knockdown the gene in metastatic RCC cell lines followed by functional assays for cellular proliferation, apoptosis and metastatic behavior. RESULTS This study identified that SFRP1 is upregulated in metastatic RCC. We found that this gene is unmethylated/hypomethylated and enriched in activating histone modifications in metastatic RCC. Apoptosis increased upon attenuation of SFRP1 expression. Also SFRP1 depletion decreased the invasive potential of the metastatic RCC cell line suggesting that the overexpression of this Wnt antagonist may be related to invasiveness and metastatic behavior in RCC. We investigated the molecular basis of the role of SFRP1 in invasion and metastasis and found that matrix metalloproteinase MMP10 is regulated by SFRP1. CONCLUSIONS Our data suggests that SFRP1 plays a role in the metastatic potential of RCC. San Francisco, CA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e142 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sharanjot Saini More articles by this author Jan Liu More articles by this author Shahana Majid More articles by this author Soichiro Yamamura More articles by this author Kazumori Kawakami More articles by this author Hiroshi Hirata More articles by this author Yuichiro Tanaka More articles by this author Peter R. Carroll More articles by this author Rajvir Dahiya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...