Nuclear expression of phosphorylated TRAF2- and NCK-interacting kinase in hepatocellular carcinoma is associated with poor prognosis

Abstract

Background and aims: 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. Conclusion: 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.