title: PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection.
abstract: BACKGROUND
  Under hypoxia, tumour cells undergo genetic and adaptive changes that allow their survival. Previously, we reported that high expression of hypoxia-inducible factor (HIF)-1 was a significant predictive factor for recurrence in hepatocellular carcinoma (HCC). Hypoxia also stimulates expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) genes via the HIF-1 pathway.
  
  
  OBJECTIVE
  The aim was to evaluate the relationship between hypoxia stress and expression of PLOD genes in HCC in vitro and to identify a new prognostic marker in HCC patients.
  
  
  METHODS
  The PLOD2 expression was assessed under hypoxia in hepatoma cell lines and characterized in 139 HCC samples following hepatic resection using microarray experiments, quantitative RT-PCR and immunohistochemistry. Prognostic factors in HCC patients were assessed using univariate and multivariate analyses.
  
  
  RESULTS
  The PLOD2 expression was induced under the hypoxia in vitro. Disease-free survival in the high PLOD2 expression group of HCC patients was significantly shorter when compared with the low-expression group (P = 0.002). In a subset of HCCs, we found that the PLOD2 expression of microarray was correlated with data of quantitative RT-PCR and immunohistochemistry. Of clinicopathological factors, PLOD2 expression was significantly correlated with tumour size (P = 0.022) and macroscopic intrahepatic metastasis (P = 0.049). In univariate analysis, six prognostic factors (tumour multiplicity, macroscopic intrahepatic metastasis, histological grade, microscopic portal invasion, microscopic intrahepatic metastasis and PLOD2 expression) were significant for disease-free survival. PLOD2 expression was identified as a significant, independent factor of poor prognosis (P = 0.013).
  
  
  CONCLUSIONS
  PLOD2 is a potential novel prognostic factor for HCC patients following surgery.
authors.affiliation: The Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Noda
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takemasa
authors.forename: Daisaku
authors.initials: D
authors.lastname: Yamada
authors.forename: Mamoru
authors.initials: M
authors.lastname: Uemura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wada
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Marubashi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tanemura
authors.forename: Koji
authors.initials: K
authors.lastname: Umeshita
authors.forename: Yuichro
authors.initials: Y
authors.lastname: Doki
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D006498:Hepatectomy; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008113:Liver Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D046228:Microarray Analysis; D009361:Neoplasm Invasiveness; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000096:biosynthesis* / Q000235:genetics; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C479138:PLOD2 protein, human; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase