title: Proteomics identified nuclear N-myc downstream-regulated gene 1 as a prognostic tissue biomarker candidate in renal cell carcinoma.
abstract: The aim of this study was to identify proteins with aberrant expression in clear cell renal cell carcinoma (ccRCC), and elucidate their clinical utilities. The protein expression profiles of primary ccRCC tumor tissues and neighboring non-tumor tissues were obtained from 9 patients by two-dimensional difference gel electrophoresis and mass spectrometry. Comparative analysis of 3771 protein spots led to the identification of 73 proteins that were expressed at aberrant levels in tumor tissues compared with non-tumor tissues. Among these 73 proteins, we further focused on N-myc downstream-regulated gene 1 protein (NDRG1). NDRG1 expression is regulated by members of myc family as well as by p53, HIF1A, and SGK1. The biological and clinical significance of NDRG1 is controversial for various malignancies and no detailed studies on NDRG1 have been reported in ccRCC until our study. For the 82 newly enrolled ccRCC patients, immunohistochemical analysis revealed a significant association between nuclear NDRG1 and favorable prognosis (p<0.05). Multivariate analysis demonstrated the role of NDRG1 as an independent factor of progression-free survival (p=0.01). Subsequent in vitro gene suppression assay demonstrated that NDRG1 silencing significantly enhanced cell proliferation and invasion of RCC cells. The cytotoxic effects of NDRG1 up-regulation induced by an iron chelator were also confirmed. These findings suggest that nuclear NDRG1 has tumor suppressive effects, and the NDRG1 expression may have clinical values in ccRCC. Nuclear NDRG1 may provide additional insights on molecular backgrounds of ccRCC progression, and contribute to the development of novel therapeutic strategy.
authors.affiliation: Division of Pharmacoproteomics, National Cancer Center Research Institute, Tokyo, Japan; Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hosoya
authors.forename: Marimu
authors.initials: M
authors.lastname: Sakumoto
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Takafumi
authors.initials: T
authors.lastname: Narisawa
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bilim
authors.forename: Teiichi
authors.initials: T
authors.lastname: Motoyama
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tomita
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C497442:HIF1A protein, human; C495901:TP53 protein, human
keywords: 2D-DIGE; N-myc downstream-regulated gene 1 protein; Prognostic tissue biomarker; Renal cell carcinoma