Functional significance of Wnt inhibitory factor-1 gene in kidney cancer.
Wnt inhibitory factor-1 (WIF-1) has been identified as one of the secreted antagonists that bind Wnt protein. WIF-1 has been described as a tumor suppressor in various types of cancer. However, the molecular function of WIF-1 gene has never been examined in human renal cell carcinoma (RCC). Therefore, we hypothesized that WIF-1 functions as a tumor suppressor gene and overexpression of this gene may induce apoptosis and inhibit tumor growth in RCC cells. Immunohistochemistry and real-time reverse transcription-PCR revealed that WIF-1 was significantly downregulated in RCC samples and RCC cell lines, respectively. Bisulfite sequencing of the WIF-1 promoter region in RCC cell lines showed it to be densely methylated, whereas there was no methylation of WIF-1 promoter in normal kidney. Significant inhibition of cell growth and colony formation in WIF-1-transfected cells compared with controls were observed. WIF-1 transfection significantly induced apoptosis and suppressed in vivo tumor growth. Also, Wnt signaling activity and beta-catenin expression were reduced by WIF-1 transfection. In conclusion, this is the first report documenting that the WIF-1 is downregulated by promoter methylation and functions as a tumor suppressor gene by inducing apoptosis in RCC cells.
Kawakami
Kazumori
K
Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California 94121, USA.
Hirata
Hiroshi
H
Yamamura
Soichiro
S
Kikuno
Nobuyuki
N
Saini
Sharanjot
S
Majid
Shahana
S
Tanaka
Yuichiro
Y
Kawamoto
Ken
K
Enokida
Hideki
H
Nakagawa
Masayuki
M
Dahiya
Rajvir
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D046888:Tissue Array Analysis; D014162:Transfection; D051153:Wnt Proteins / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins