Clinical Research Papers:

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 and Hiroaki Shiina

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Oncotarget. 2015; 6:9577-9591. https://doi.org/10.18632/oncotarget.3445

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Yozo Mitsui1,2, Hiroshi Hirata2, Naoko Arichi1, Miho Hiraki1, Hiroaki Yasumoto1, Inik Chang3, Shinichiro Fukuhara4, Soichiro Yamamura2, Varahram Shahryari2, Guoren Deng2, Sharanjot Saini2, Shahana Majid2, Rajvir Dahiya2, Yuichiro Tanaka2 and Hiroaki Shiina1

1 Department of Urology, Shimane University Faculty of Medicine, Enya-cho, Izumo, Japan

2 Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California, USA

3 Department of Oral Biology, Yonsei University College of Densitry, Seoul, South Korea

4 Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan

Correspondence to:

Yozo Mitsui, email:

Keywords: bone morphogenetic protein 2, renal cell carcinoma, DNA methylation, molecular marker

Received: January 15, 2015 Accepted: February 10, 2015 Published: March 07, 2015


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 p21WAF1/CIP1 and p27KIP1 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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