title: Frequent epigenetic suppression of tumor suppressor gene glutathione peroxidase 3 by promoter hypermethylation and its clinical implication in clear cell renal cell carcinoma.
abstract: The goal of this study is to identify novel tumor suppressor genes silenced by promoter methylation in clear cell renal cell carcinoma (ccRCC) and discover new epigenetic biomarkers for early cancer detection. Reactive oxygen species (ROS) is a major cause of DNA damage that correlates with cancer initiation and progression. Glutathione peroxidase 3 (GPX3), the only known extracellular glycosylated enzyme of GPXs, is a major scavenger of ROS. GPX3 has been identified as a tumor suppressor in many cancers. However, the role of GPX3 in ccRCC remains unclear. This study aimed to investigate its epigenetic alteration in ccRCC and possible clinicopathological association. In our study, GPX3 methylation and down-regulation were detected in 5 out of 6 ccRCC cell lines and the GPX3 mRNA and protein expression level in ccRCC tumors was significantly lower than in adjacent non-malignant renal tissues (p<0.0001). Treatment with 5-Aza-2'-deoxycytidine restored GPX3 expression in ccRCC cells. Aberrant methylation was further detected in 77.1% (162/210) of RCC primary tumors, but only 14.6% (7/48) in adjacent non-malignant renal tissues. GPX3 methylation status was significantly associated with higher tumor nuclear grade (p=0.014). Thus, our results showing frequent GPX3 inactivation by promoter hypermethylation in ccRCC may reveal the failure in the cellular antioxidant system in ccRCC and may be associated with renal tumorigenesis. GPX3 tumor specific methylation may serve as a biomarker for early detection and prognosis prediction of ccRCC.
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. lqlbjmu@163.com.
authors.forename: Qianling
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. jinjie@vip.163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pathology, Cancer Institute and Cancer Hospital, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences, Beijing 100021, China. jmying@hotmail.com.
authors.forename: Jianming
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. wkdsmk@163.com.
authors.forename: Mengkui
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. cuiyunbjmu@163.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. hays0324@163.com.
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. xuben123457890@163.com.
authors.forename: Ben
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. dantefanbmu@126.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China. zhangqian@bjmu.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: C486484:GPX3 protein, human; D005979:Glutathione Peroxidase
keywords: GPX3; clear cell renal cell carcinoma; methylation; reactive oxygen species; tumor suppress gene