1061 ACTIVATION OF THE ARYL HYDROCARBON RECEPTOR PATHWAY ENHANCES CANCER CELL INVASION BY UP-REGULATING THE MMP EXPRESSION IN UROTHELIAL CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research1 Apr 20111061 ACTIVATION OF THE ARYL HYDROCARBON RECEPTOR PATHWAY ENHANCES CANCER CELL INVASION BY UP-REGULATING THE MMP EXPRESSION IN UROTHELIAL CANCER Masaru Ishida, Shuji Mikami, Eiji Kikuchi, Takeo Kosaka, Akira Miyajima, Makio Mukai, Yasunori Okada, and Mototsugu Oya Masaru IshidaMasaru Ishida Tokyo, Yokohama, Japan More articles by this author , Shuji MikamiShuji Mikami Tokyo, Japan More articles by this author , Eiji KikuchiEiji Kikuchi Tokyo, Japan More articles by this author , Takeo KosakaTakeo Kosaka Tokyo, Japan More articles by this author , Akira MiyajimaAkira Miyajima Tokyo, Japan More articles by this author , Makio MukaiMakio Mukai Tokyo, Japan More articles by this author , Yasunori OkadaYasunori Okada Tokyo, Japan More articles by this author , and Mototsugu OyaMototsugu Oya Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1098AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Aryl hydrocarbon receptor (AhR) is a receptor for xenobiotics, and the activation of its pathway is associated with xenobiotic-induced toxicity. The activated AhR induces the expression of genes coding for xenobiotic metabolizing enzymes, such as cytochrome P450s (CYPs), which are involved in the activation of procarcinogens. Exposure to the xenobiotics, such as cigarette smoke, is associated with urothelial cancer (UC). In addition, we previously reported that AhR expression is significantly associated with the pT stage, nuclear grade and lymphovascular invasion in upper urinary tract UC, and AhR expression is a significant and independent predictor for the disease-specific survival. However, the molecular mechanism by which the activation of the AhR pathway contributes to the malignant progression of UC is still unclear. The aim of this study is to elucidate the role of AhR in an UC cell by regulating the expression with its ligand or siRNA in vitro. METHODS T24 cells, a UC cell line, were exposed to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR to activate the AhR pathway. Subsequently, AhR expression was down-regulated by transfection of small interfering RNA (siRNA) for AhR. The AhR activation status was examined by investigating the expression of CYPs using real time RT-PCR. Furthermore, the expression of matrix metalloproteinases (MMPs) and cell invasion through Matrigel™ in vitro were also investigated. RESULTS TCDD treatment up-regulated the expression levels of AhR, CYP1A1 and CYP1B1 by 50.0, 73.0 and 38.1%, respectively (P < 0.05), and it also enhanced the invasion of T24 cells by 68.5% (P < 0.05) together with the up-regulation of matrix metalloproteinase (MMP) -1 and MMP-9 by 187.6 and 98.3%, respectively (P < 0.05). Furthermore, siRNA for AhR down-regulated the mRNA expression of AhR, CYP1A1, CYP1B1, MMP-1, MMP-2 and MMP-9 in T24 cells by 89.0, 78.1, 75.9, 92.3, 21.8 and 94.8%, respectively (P < 0.05). The cells transfected with siRNA for AhR showed a decreased invasion activity in comparison to those transfected with a non-targeting siRNA by 52.8% (P < 0.05). CONCLUSIONS These results suggest that the activation of the AhR pathway accelerates cancer cell invasion by inducing MMPs, and AhR could therefore be a potentially attractive therapeutic target for the control of urinary tract UC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e426 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masaru Ishida Tokyo, Yokohama, Japan More articles by this author Shuji Mikami Tokyo, Japan More articles by this author Eiji Kikuchi Tokyo, Japan More articles by this author Takeo Kosaka Tokyo, Japan More articles by this author Akira Miyajima Tokyo, Japan More articles by this author Makio Mukai Tokyo, Japan More articles by this author Yasunori Okada Tokyo, Japan More articles by this author Mototsugu Oya Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...