Peritumoral overexpression of ZBP-89 is associated with unfavorable disease-free survival rates in patients with hepatocellular carcinoma following hepatectomy

Abstract

Previous studies have revealed that the peritumoral environment has a profound influence on tumor initiation and progression. Zinc-binding protein-89 (ZBP-89) has been observed to be involved with tumor development, recurrence, and metastasis. High intratumoral expression of ZBP-89 has been associated with improved prognosis in several tumor types. However, the prognostic values of peritumoral expression of ZBP-89 remain to be elucidated in patients with hepatocellular carcinoma (HCC) following curative resection. In the present study, peritumoral ZBP-89 expression was examined using immunohistochemistry in 102 HCC patients who had received curative hepatectomy. Expression of ZBP-89 protein was positive in 66.3% of the peritumoral samples from 102 HCC patients. HCC patients with high peritumoral ZBP-89 expression exhibited significantly shorter disease-free survival (DFS) times (P=0.012) than those patients with low peritumoral ZBP-89 expression. Additionally, high ZBP-89 expression in peritumoral HCC tissue was positively associated with the presence of liver cirrhosis. Univariate and multivariate Cox proportional hazard regression analyses demonstrated that albumin levels ≤35 g/l, multiple tumors, tumor sizes ≥5 cm, and macroscopic vascular invasion may serve as independent prognostic factors for overall survival (OS) [hazard ratio (HR)=2.031; P=0.014] in patients with HCC. The multivariate Cox regression model identified that high ZBP-89 expression, multiple tumors and macroscopic vascular invasion were independent prognostic factors for shorter DFS durations. High expression of ZBP-89 in peritumoral HCC tissues was associated with a shorter DFS in HCC patients following curative hepatectomy. Additionally, high ZBP-89 expression in peritumoral HCC tissue was positively associated with the presence of liver cirrhosis in HCC patients, indicating that cirrhosis accompanied by high ZBP-89 expression may be a contributing factor to the poor prognosis of patients with HCC. Therefore, peritumoral ZBP-89 expression may be a good prognostic marker to predict DFS time in HCC patients following curative hepatectomy and may provide novel insights into the molecular mechanisms of HCC initiation.

Keywords: ZBP-89; hepatocellular carcinoma; peritumoral; prognosis.

Figure 1.

Immunohistochemical analysis of ZBP-89 in peritumoral liver tissues. (A) Negative peitumoral cytoplasmic/nuclei staining for ZBP-89. (B) High peritumoral cytoplasmic and nuclear staining for ZBP-89. (C) High peritumoral cytoplasmic staining for ZBP-89. (D) High peritumoral nuclear staining for ZBP-89. (E) Protein levels of ZBP-89 in six HCC peritumoral tissues, three of which exhibit high expression of ZBP-89 by IHC and three exhibiting low expression. ZBP-89, zinc-binding protein-89.

Figure 2.

Prognostic values of the peritumoral hepatocellular expression of ZBP-89. Kaplan-Meier (A) DFS and (B) OS rate analysis of ZBP-89 in 102 patients with HCC who had received curative hepatectomy. Prognostic values of the subcellular localization of ZBP-89 expression in peritumoral hepatocytes. All patients were classified into 4 subgroups: Cytoplasmic type (n=60); nuclear type (n=14); cytoplasmic and nuclear type (n=8); as well as negative (n=20). Kaplan-Meier analysis of (C) DFS and (D) OS with 4 subgroups in the peritumoral liver tissue; Prognostic values of the METAVIR scores in peritumoral liver tissue. All patients were classified into 3 subgroups: F0-1 (n=15); F1-2 (n=28); and F3-4 (n=58). Kaplan-Meier analysis of (E) DFS and (F) OS with 3 subgroups in the peritumoral liver tissue. ZBP-89, zinc-binding protein-89; DFS, disease-free survival; OS, overall survival.