title: Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways.
abstract: We investigated whether impaired regulation of bone morphogenetic protein-2 (BMP-2) via epigenetic pathways is associated with renal cell carcinoma (RCC) pathogenesis. Expression and CpG methylation of the BMP-2 gene were analyzed using RCC cell lines, and 96 matched RCC and normal renal tissues. We also performed functional analysis using BMP-2 restored RCC cells. A significant association of BMP-2 mRNA expression was also found with advanced tumor stage and lymph node involvement, while lower BMP-2 mRNA expression was significantly associated with poor overall survival after radical nephrectomy. In RCC cells, BMP-2 restoration significantly inhibited cell proliferation, migration, invasion, and colony formation. In addition, BMP-2 overexpression induced p21(WAF1/CIP1) and p27(KIP1) expression, and cellular apoptosis in RCC cells. BMP-2 mRNA expression was significantly enhanced in RCC cells by 5-aza-2'-deoxycitidine treatment. The prevalence of BMP-2 promoter methylation was significantly greater and BMP-2 mRNA expression was significantly lower in RCC samples as compared to normal kidney samples. Furthermore, a significant correlation was found between BMP-2 promoter methylation and mRNA transcription in tumors. Aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be a useful molecular marker for designing improved diagnostic and therapeutic strategies for RCC.
authors: Department of Urology, Shimane University Faculty of Medicine, Enya-cho, Izumo, Japan.|Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Yozo
authors: Y
authors: Mitsui
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Hiroshi
authors: H
authors: Hirata
authors: Department of Urology, Shimane University Faculty of Medicine, Enya-cho, Izumo, Japan.
authors: Naoko
authors: N
authors: Arichi
authors: Department of Urology, Shimane University Faculty of Medicine, Enya-cho, Izumo, Japan.
authors: Miho
authors: M
authors: Hiraki
authors: Department of Urology, Shimane University Faculty of Medicine, Enya-cho, Izumo, Japan.
authors: Hiroaki
authors: H
authors: Yasumoto
authors: Department of Oral Biology, Yonsei University College of Densitry, Seoul, South Korea.
authors: Inik
authors: I
authors: Chang
authors: Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Shinichiro
authors: S
authors: Fukuhara
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Soichiro
authors: S
authors: Yamamura
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Varahram
authors: V
authors: Shahryari
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Guoren
authors: G
authors: Deng
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Sharanjot
authors: S
authors: Saini
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Shahana
authors: S
authors: Majid
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Rajvir
authors: R
authors: Dahiya
authors: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA.
authors: Yuichiro
authors: Y
authors: Tanaka
authors: Department of Urology, Shimane University Faculty of Medicine, Enya-cho, Izumo, Japan.
authors: Hiroaki
authors: H
authors: Shiina
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000601:surgery; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018816:Genes, cdc; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000601:surgery; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D009392:Nephrectomy; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D000077209:Decitabine; D001374:Azacitidine
keywords: DNA methylation; bone morphogenetic protein 2; molecular marker; renal cell carcinoma