title: Overexpression of NDRG1 is an indicator of poor prognosis in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma is a highly lethal cancer that typically has poor prognosis. Prognostic markers can help in its clinical management and in understanding the biology of poor prognosis. Through an earlier gene expression study, we identified N-Myc downregulated gene 1 (NDRG1) to be significantly highly expressed in hepatocellular carcinoma compared to nontumor liver. As NDRG1 is a differentiation-related gene with putative metastasis suppressor activity, we investigated the clinical significance of its overexpression. Quantitative real-time polymerase chain reaction using an independent set of patient samples confirmed the significant overexpression of NDRG1 in hepatocellular carcinoma compared to nontumor liver samples (P<0.001). Additionally, high levels of NDRG1 transcript correlated with shorter overall survival (P<0.001), late tumor stage (P=0.001), vascular invasion (P=0.003), large tumor size (P=0.011), and high Edmondson-Steiner histological grade (P=0.005). Using immunohistochemistry, NDRG1 protein was found to be significantly overexpressed in hepatocellular carcinoma samples compared to nontumor liver or cirrhotic and benign liver lesions (P<0.001). Among the hepatocellular carcinoma samples, those which are moderately and poorly differentiated express higher levels of NDRG1 protein than those which are well-differentiated (P<0.005). Additionally, hepatocellular carcinomas with vascular invasion also express elevated levels of NDRG1 protein compared to those without vascular invasion (significant at P<0.005). Our results suggest NDRG1 to be a likely tumor marker for hepatocellular carcinoma, the overexpression of which is correlated with tumor differentiation, vascular invasion, and overall survival. Its significantly elevated expression in hepatocellular carcinoma could be a useful indicator of tumor aggressiveness and therefore patient prognosis.
authors.affiliation: Department of Surgery and Asian Liver Center, Stanford University School of Medicine, Stanford, CA, USA. mchua@stanford.edu
authors.forename: Mei-Sze
authors.initials: MS
authors.lastname: Chua
authors.forename: Hongbo
authors.initials: H
authors.lastname: Sun
authors.forename: Siu T
authors.initials: ST
authors.lastname: Cheung
authors.forename: Veronica
authors.initials: V
authors.lastname: Mason
authors.forename: John
authors.initials: J
authors.lastname: Higgins
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Ross
authors.forename: Sheung T
authors.initials: ST
authors.lastname: Fan
authors.forename: Samuel
authors.initials: S
authors.lastname: So
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000235:genetics; D002454:Cell Differentiation; D015331:Cohort Studies; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis* / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000032:analysis; D015203:Reproducibility of Results; D013997:Time Factors; D046888:Tissue Array Analysis; D015854:Up-Regulation; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D000099259:N-myc Downstream-Regulated Gene 1 Protein