title: Dihydropyrimidinase-like 3 is a putative hepatocellular carcinoma tumor suppressor.
abstract: BACKGROUND
  Patients with hepatocellular carcinoma (HCC) may relapse after curative resection. Sensitive biomarkers for HCC are required to enhance disease management. Dihydropyrimidinase-like 3 (DPYSL3) suppresses cell proliferation and tumorigenicity of certain malignancies; however, its role in HCC is unknown.
  
  
  METHODS
  The expression levels of DPYSL3 and genes encoding potential interacting proteins vascular endothelial growth factor (VEGF), focal adhesion kinase (FAK), ezrin, and cellular src were determined using RT-PCR. Further, we determined the methylation status of the DPYSL3 promoter in HCC cells lines and the effect of inhibiting DPYSL3 expression on their phenotype. DPYSL3 expression was determined in 151 pairs of resected liver tissues.
  
  
  RESULTS
  DPYSL3 mRNA levels were down-regulated in most HCC cell lines with DPYSL3 promoter hypermethylation, and expression was restored after demethylation. DPYSL3 expression levels inversely correlated with those of VEGF and FAK. Knockdown of DPYSL3 significantly increased migration and the invasive properties of HCC cells. The mean level of DPYSL3 mRNA was significantly lower in HCC tissues compared with corresponding noncancerous tissues. The expression patterns of DPYSL3 mRNA and protein were consistent. DPYSL3 mRNA expression in HCC tissues inversely correlated with preoperative serum tumor markers and was significantly lower in patients with extrahepatic recurrences. Disease-specific and recurrence-free survival was significantly shorter in patients with down-regulated DPYSL3 expression.
  
  
  CONCLUSIONS
  Our results indicate that DPYSL3 is a putative HCC tumor suppressor, and promoter hypermethylation potently regulates DPYSL3 transcription. Down-regulation of DPYSL3 expression in HCC tissues may serve as a predictive biomarker for HCC after curative resection.
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Hisaharu
authors.initials: H
authors.lastname: Oya
authors.forename: Mitsuro
authors.initials: M
authors.lastname: Kanda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Dai
authors.initials: D
authors.lastname: Shimizu
authors.forename: Hideki
authors.initials: H
authors.lastname: Takami
authors.forename: Soki
authors.initials: S
authors.lastname: Hibino
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hashimoto
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Okamura
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.forename: Goro
authors.initials: G
authors.lastname: Nakayama
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koike
authors.forename: Shuji
authors.initials: S
authors.lastname: Nomoto
authors.forename: Michitaka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006785:Hospitals, University; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C102926:DPYSL3 protein, human; D009124:Muscle Proteins; D042461:Vascular Endothelial Growth Factor A; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human