title: Nuclear expression of phosphorylated TRAF2- and NCK-interacting kinase in hepatocellular carcinoma is associated with poor prognosis.
abstract: OBJECTIVE
  TRAF2- and NCK-interacting kinase (TNIK) is a member of the germinal center kinase family and a transcription factor 4 (TCF4) interactor is recruited to promoters of Wnt target genes via phosphorylation of the TCF/β-catenin complex. The aim of this study was to evaluate the TNIK, the active form of TNIK (p-TNIK), and β-catenin expression in hepatocellular carcinoma (HCC), and to identify the prognostic significance of p-TNIK.
  
  
  METHODS
  We assessed the expression status of TNIK, p-TNIK, and β-catenin by using immunohistochemical analysis of 302 HCCs in 8 tissue microarray blocks, and we evaluated their clinicopathologic features and survival rates based on their p-TNIK expression.
  
  
  RESULTS
  Of 302 HCCs, 92.7% stained positive for TNIK in the cytoplasm. Nuclear expression of p-TNIK was identified in 7.9% HCCs. Aberrant cytoplasmic expression of β-catenin was identified in 77.2% and nuclear expression in 3.3%. p-TNIK nuclear staining was positively correlated to β-catenin nuclear expression (P=0.036). Cytoplasmic and nuclear expression of p-TNIK was more frequently observed in high Edmondson-Steiner (ES) nuclear grade groups (P=0.030). Nuclear p-TNIK expression was also associated with pathological M1 stage (pM1 stage) patients (P<0.0001). Aberrant cytoplasmic expression of β-catenin was more frequently identified in larger tumors (P=0.014). Univariate (DFS, P=0.049; OS, 0.037) and multivariate analysis (DFS, P=0.006; OS, P=0.003) confirmed the independent prognostic significance of nuclear p-TNIK expression.
  
  
  CONCLUSIONS
  This is the first time that nuclear p-TNIK expression was studied in HCC, and p-TNIK nuclear expression was associated with poor prognosis and is a candidate prognostic marker for HCC.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Hae Yoen
authors.initials: HY
authors.lastname: Jung
authors.affiliation: Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Xie
authors.affiliation: Korea Research Institute of Bioscience & Biotechnology, 125 Gwahangno, Daejeon 304-806, Republic of Korea.
authors.forename: Yong Il
authors.initials: YI
authors.lastname: Yeom
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Republic of Korea; Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea.
authors.forename: Ja-June
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Republic of Korea. Electronic address: azirang@chol.com.
authors.forename: Kyong Bun
authors.initials: KB
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D000081410:Germinal Center Kinases; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D000081410:Germinal Center Kinases; D047992:TNF Receptor-Associated Factor 2; D051153:Wnt Proteins; D051176:beta Catenin; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human
keywords: HCC; Prognosis; p-TINK nuclear expression