title: NRD1, which encodes nardilysin protein, promotes esophageal cancer cell invasion through induction of MMP2 and MMP3 expression.
abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. In the present study, to identify novel prognostic markers or therapeutic targets for ESCC, we reviewed a list of genes with upregulated expression in ESCC compared with normal esophagus, as identified by our serial analysis of gene expression (SAGE) analysis. We focused on the NRD1 gene, which encodes the nardilysin protein. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) in 34 ESCC tissue samples revealed that mRNA expression of NRD1 was upregulated in 56% of ESCC tissue samples. Immunohistochemical analysis of nardilysin in 109 ESCC tissue samples demonstrated that 43 (39%) ESCC cases were positive for nardilysin. Nardilysin-positive ESCC cases were more advanced in terms of T classification (P = 0.0007), N classification (P = 0.0164), and tumor stage (P < 0.0001) than nardilysin-negative ESCC cases. Furthermore, nardilysin expression was significantly associated with poorer prognosis (P = 0.0258). Univariate and multivariate analyses revealed that nardilysin expression is an independent prognostic classifier of patients with ESCC. The invasiveness of NRD1-knockdown TE1 and TE5 esophageal cancer cell lines was less than that of the negative control siRNA-transfected cell lines. Expression of MMP2 and MMP3 mRNA was significantly lower in NRD1-knockdown TE5 cells than in negative control siRNA-transfected cells. These results suggest that nardilysin is involved in tumor progression, and is an independent prognostic classifier in patients with ESCC.
authors.affiliation: Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Uraoka
authors.forename: Naohide
authors.initials: N
authors.lastname: Oue
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sentani
authors.forename: Htoo Zarni
authors.initials: HZ
authors.lastname: Oo
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Naito
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Noguchi
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011379:Prognosis; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D008666:Metalloendopeptidases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C570669:NRDC protein, human; C087976:nardilysin
keywords: Esophageal cancer; NRD1; invasion; nardilysin; prognosis