109 DKK4 ACTIVATES NON-CANONICAL JNK SIGNALING PATHWAY WHILE INHIBITING THE WNT-CANONICAL PATHWAY IN HUMAN RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research1 Apr 2011109 DKK4 ACTIVATES NON-CANONICAL JNK SIGNALING PATHWAY WHILE INHIBITING THE WNT-CANONICAL PATHWAY IN HUMAN RENAL CELL CARCINOMA Hiroshi Hirata, Koji Ueno, Koichi Nakajima, Laura Tabatabai, Yuji Hinoda, Nobuhisa Ishii, Peter Carroll, and Rajvir Dahiya Hiroshi HirataHiroshi Hirata San Francisco, CA More articles by this author , Koji UenoKoji Ueno San Francisco, CA More articles by this author , Koichi NakajimaKoichi Nakajima Ohtaku, Japan More articles by this author , Laura TabatabaiLaura Tabatabai San Francisco, CA More articles by this author , Yuji HinodaYuji Hinoda Ube, Japan More articles by this author , Nobuhisa IshiiNobuhisa Ishii Ohtaku, Japan More articles by this author , Peter CarrollPeter Carroll San Francisco, CA More articles by this author , and Rajvir DahiyaRajvir Dahiya San Francisco, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.175AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal cell carcinoma (RCC) is the third leading cause of death among urological tumors. Although the rate of detection of incidental RCC has increased with improved diagnostic techniques, metastatic lesions are still found at diagnosis in about 30% of RCC patients.Wnt/beta-catenin signaling, which is one of important cancer pathways, includes beta-catenin dependent and independent pathways. The functional significance of some Wnt antagonists has been reported in renal cancer. However the functional significance of Wnt antagonist DKK4 has not been investigated in RCC. Recently DKK4 function has been reported to have two opposing functions (oncogenic /tumor suppressor) in colon cancer by different research groups. As far as we know, there have been no reports regarding DKK4 and RCC. METHODS We initially found that the expression of DKK4 was significantly higher in renal cancer tissues compared to adjacent normal kidney tissues. To assess the function of DKK4, we established stable DKK4 transfected cells and performed functional analyses including TCF/LEF reporter assay. RESULTS The relative TCF/LEF activity was significantly lower in DKK4 transfected cells compared to empty vector, and nuclear beta-catenin expression was decreased in DKK4 transfectants. Also beta-catenin downstream effector proteins, cyclinD1 and c-Myc, showed decreased expression in DKK4 transfectants. This result indicates that DKK4 is a beta-catenin dependent pathway inhibitor. However, higher invasiveness and migration was observed in stably transfected DKK4 cells and DKK4 promoted tumor growth in vitro and in vivo. To investigate the oncogenic function in DKK4 transfectants, we focused on the Wnt non-canonical/JNK signaling pathway. We found that phosphorylation of JNK, expression and phosphorylation of c-Jun were increased in DKK4 transfected A-498 cells. MMP-2 expression was also significantly increased in DKK4 stable transfectants. CONCLUSIONS This is the first report documenting that DKK4 expression is higher in renal cancer tissues compared to matched normal kidney tissues. DKK4 inhibited the canonical pathway. Though DKK4 did not induce apoptosis it promoted renal cancer cell proliferation, invasion, and migration via the non-canonical JNK pathway, which also increased MMP-2 expression. Thus the current findings contribute significant information about the role of DKK4 in renal cancer cells. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e46 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiroshi Hirata San Francisco, CA More articles by this author Koji Ueno San Francisco, CA More articles by this author Koichi Nakajima Ohtaku, Japan More articles by this author Laura Tabatabai San Francisco, CA More articles by this author Yuji Hinoda Ube, Japan More articles by this author Nobuhisa Ishii Ohtaku, Japan More articles by this author Peter Carroll San Francisco, CA More articles by this author Rajvir Dahiya San Francisco, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...