Down-regulation of osteoprotegerin expression as a novel biomarker for colorectal carcinoma
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Hyun-Soo Kim1, Gun Yoon2, Sung-Im Do3, Sung-Joo Kim4, Youn-Wha Kim5
1Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
2Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea
3Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
4Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
5Department of Pathology, Kyung Hee University School of Medicine, Seoul, Republic of Korea
Youn-Wha Kim, e-mail: [email protected]
Keywords: osteoprotegerin, down-regulation, colorectal carcinoma, promoter methylation
Received: September 10, 2015 Accepted: January 31, 2016 Published: March 03, 2016
A better understanding of tumor biology is important in the identification of molecules that are down-regulated in malignancy and in determining their role in tumor suppression. The aim of this study was to analyze osteoprotegerin (OPG) expression in colorectal carcinoma (CRC) and to investigate the underlying mechanism for changes in the expression of OPG. OPG expression was assessed in CRC tissue samples and cell lines. The methylation status of the OPG promoter region was determined, and the effects of demethylation on OPG expression were analyzed. The effects of recombinant OPG (rOPG) administration on cellular functions were also investigated. Clinical and prognostic implications of OPG protein expression in CRC patients were analyzed. The CRC tissues and cells showed significantly lower OPG expression. Pyrosequencing of OPG-silenced CRC cells revealed that the OPG gene promoter was highly methylated. Treatment with demethylating agent significantly elevated OPG mRNA and protein expression. rOPG significantly decreased cell viability and MMP-2 and VEGF-A production in CRC cells. Reduced OPG immunoreactivity was associated with aggressive oncogenic behavior in CRC. Also, OPG expression was found to be an independent predictor of recurrent hepatic metastasis and independent prognostic factor for worse survival rates. We demonstrated that OPG silencing in CRC occurs through epigenetic repression, and is involved in the development and progression of CRC. Our data suggest that OPG is a novel prognostic biomarker and a new therapeutic target for the treatment of patients with CRC.
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