High STAT4 Expression is a Better Prognostic Indicator in Patients with Hepatocellular Carcinoma After Hepatectomy

Abstract

Background: Signal transducer and activator of transcription 4 (STAT4) mediates the intracellular effects of interleukin-12, leading to the production of interferon gamma (IFN-γ) and natural killer cells cytotoxicity. However, the clinical significance of STAT4 expression in patients with hepatocellular carcinoma (HCC) remains virtually unknown. Methods: A total of 66 HCC patients who underwent hepatectomy were enrolled in this study. Quantitative real-time polymerase chain reaction was performed to determine STAT4 and IFNG mRNA expression levels. Tissue microarray-based immunohistochemistry was performed to examine CD8 + T cells, STAT4, and INF-γ proteins. Results: STAT4 was differentially expressed in tumor and nontumor tissues (P = 0.001) and positively correlated with IFNG expression (R 2 = 0.506, P < 0.05) and CD8 + T cell infiltration (R 2 = 0.53, P < 0.001). Significant correlations were observed between STAT4 expression and tumor TNM stage (P = 0.043), hepatic venous invasion (P = 0.003), des-gamma-carboxy prothrombin (P = 0.011), tumor size (P = 0.036), and tumor differentiation (P = 0.034). Patients with high STAT4 expression had significantly better recurrence-free survival (P = 0.009). Low STAT4 expression (P = 0.030) and presence of portal venous invasion or hepatic venous invasion (P = 0.006) were independent risk factors for HCC recurrence. Conclusions: Downregulation of STAT4 in HCC indicated aggressive tumor behavior and predicted a worse clinical outcome. STAT4 might be a useful biomarker to identify patients at high risk of recurrence after hepatectomy.