Abstract
Heterogeneous ribonucleoproteinA1 (hnRNPA1) is a documented tumor biomarker known to be aberrantly expressed in a number of types of human cancer. However, to the best of our knowledge, its prognostic value for surgically resected HCC (RHCC) in the high incidence areas of China has not been described; the association between hnRNPA1 expression, pre-operative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) is also not understood. In the present study, hnRNPA1 expression was retrospectively measured in two independent cohorts of patients with hepatocellular carcinoma (HCC) who underwent surgery to remove the primary cancer at one center in Fujian, an area with a high incidence of HCC in China. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemistry (IHC) were used to quantify hnRNPA1 expression in RHCC tissues. The survival curves were plotted using the Kaplan-Meier method, and the prognostic significance of hnRNPA1, NLR and PLR was analyzed using the log-rank test. The relevant prognostic factors were identified by multivariate Cox regression analysis. RT-qPCR and western blotting revealed that hnRNPA1 was upregulated in HCC tissues (P<0.001), and particularly overexpressed in tumor tissues of patients with recurrent HCC (P<0.001) (cohort 1; 54 patients). Differential hnRNPA1 expression was measured in 426HCC tissues with IHC; 259 exhibited high hnRNPA1 expression and 167 exhibited low expression. High hnRNPA1 expression was significantly associated with Tumor-Node-Metastasis stage (P=0.024), tumor size (P=0.027), vascular invasion (P<0.001), Edmonson grade (P<0.001), pre-operative serum α-fetoprotein (AFP) (P<0.001), NLR (P<0.001) and PLR (P<0.001). In addition, multivariate Cox regression analysis confirmed that high hnRNPA1 expression was associated with relapse-free survival (RFS; HR, 0.685; 95% CI, 0.506-0.928; P=0.015) and overall survival (OS; HR, 0.629; 95% CI, 0.454-0.871; P=0.005). Multivariate analysis confirmed that higher pre-operative serum AFP had an unfavorable impact on RFS (HR, 1.350; 95% CI, 1.006-1.811; P=0.045) and OS (HR=1.564; 95% CI, 1.151-2.126; P=0.004), while higher pre-operative NLR had an unfavorable impact on OS (HR, 1.758; 95% CI, 1.161-2.661; P=0.008) (cohort 2;426 patients). The expression of hnRNPA1 was also positively correlated with NLR (Spearman's correlation; r=0.122, P=0.012) and PLR (Spearman's correlation; r=0.140, P=0.004). In conclusion, high hnRNPA1 expression was revealed as prognostic for poor survival in patients with RHCC, and detection of hnRNPA1 protein in tumor tissues demonstrated potential in estimating survival for patients with RHCC in areas with high incidence rates. Furthermore, the combination of high hnRNPA1 expression and pre-operative serum AFP levels (>400 µg) proved to be a good diagnostic and prognostic biomarker for this specific population of patients. Finally, a correlation may also exist between hnRNPA1 expression and other markers of systemic inflammation.