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Inactivation of bone morphogenetic protein 2 may predict clinical outcome and poor overall survival for renal cell carcinoma through epigenetic pathways.

 Yozo Mitsui  ;  Hiroshi Hirata  ;  Naoko Arichi  ;  Miho Hiraki  ;  Hiroaki Yasumoto  ;  Inik Chang  ;  Shinichiro Fukuhara  ;  Soichiro Yamamura  ;  Varahram Shahryari  ;  Guoren Deng  ;  Sharanjot Saini  ;  Shahana Majid  ;  Rajvir Dahiya  ;  Yuichiro Tanaka  ;  Hiroaki Shiina 
 ONCOTARGET , Vol.6(11) : 9577-9591, 2015 
Journal Title
Issue Date
Aged ; Antimetabolites, Antineoplastic/pharmacology ; Apoptosis ; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Bone Morphogenetic Protein 2/biosynthesis ; Bone Morphogenetic Protein 2/genetics* ; Carcinoma, Renal Cell/genetics* ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/mortality ; Carcinoma, Renal Cell/surgery ; Cell Line, Tumor ; DNA Methylation*/drug effects ; Down-Regulation ; Female ; Gene Expression Regulation, Neoplastic*/drug effects ; Genes, cdc ; Humans ; Kidney Neoplasms/genetics* ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/mortality ; Kidney Neoplasms/surgery ; Kidney Tubules/metabolism ; Male ; Middle Aged ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics* ; Nephrectomy ; Promoter Regions, Genetic/drug effects ; Promoter Regions, Genetic/genetics ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; RNA, Neoplasm/biosynthesis ; RNA, Neoplasm/genetics ; Recombinant Fusion Proteins/biosynthesis ; Recombinant Fusion Proteins/genetics ; Transfection ; Treatment Outcome
DNA methylation ; bone morphogenetic protein 2 ; molecular marker ; renal cell carcinoma
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.
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2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Chang, In Ik(장인익)
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