Abstract
BACKGROUND: Citrullination is a post-translational modification mediated by calcium-dependent peptidylarginine deiminases that results in notable changes in protein structure and function. Glial fibrillary acidic protein (GFAP), which is highly vulnerable to peptidylarginine deiminases-mediated modification, has been found to be elevated in activated hepatic stellate cells, with GFAP-positive hepatic stellate cells and myofibroblasts accumulating within and around areas of hepatic fibrosis. Although recent studies have shown that the expression of citrullinated GFAP (cit-GFAP) increases during hepatic fibrosis, its expression pattern and functional roles in hepatocellular carcinoma (HCC) remain unclear. AIM: To determine whether cit-GFAP expression influences the recurrence and survival of patients undergoing hepatic resection for HCC. METHODS: We retrospectively analyzed 169 patients with HCC who underwent hepatic resection. Based on the immunohistochemical staining of resected specimens, the enrolled patients were stratified into two groups according to cit-GFAP expression: Low (-/1 +) or high (2 +/3 +) levels of expression. Kaplan-Meier survival curves were constructed to assess overall survival and recurrence-free survival, and comparisons between groups were performed using the log-rank test. RESULTS: The median follow-up duration was 33 months (range, 1-183). High cit-GFAP expression, identified in 81 patients (48.2%), was significantly associated with male sex, hepatitis B virus positivity, and higher Edmonson-Steiner grade. No associations were found between age, diabetes, hypertension, cirrhosis, Child-Pugh classification, major portal vein invasion, hematological or biochemical parameters, tumor size, or number. Patients exhibiting high cit-GFAP expression demonstrated significantly poorer overall survival. Multivariate Cox analysis identified large tumor size (hazard ratio: 2.967; 95% confidence interval: 1.097-8.024; P = 0.032) and high cit-GFAP expression (hazard ratio: 2.753; 95% confidence interval: 1.015-7.464; P = 0.047) as independent predictors of poor postoperative survival. Although recurrence rates were high in patients with high cit-GFAP expression, the difference was not statistically significant. CONCLUSION: Following curative resection in patients with HCC, high cit-GFAP expression may serve as a potential prognostic biomarker, although further validation through independent cohort studies is warranted.