Objectives: Hepatocellular carcinoma (HCC) patients at the same stage exhibit different prognosis, and the underlying molecular mechanism remains unclear. This study aims to identify the key genes impacting the prognosis of HCC patients.

Methods: Differentially expressed gene analyses were performed between HCC samples and normal ones, and between patients with long overall survival (OS) and those with short OS, in TCGA-LIHC and GSE14520 datasets. The Kaplan-Meier method with log-rank test was used to evaluate the role of secreted phosphoprotein 2 (SPP2) in the prognosis of HCC patients. Gene set enrichment analysis (GSEA) was used to understand the difference of enriched signaling pathways between SPP2-stratified HCC subgroups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the potential functional pathways in which SPP2 might participate.

Results: SPP2 was significantly down-regulated in tumors when compared with normal tissues, or in tumor samples with short OS when compared with those with long OS [fold change (FC)>2 and false discovery rate (FDR)<0.05]. Low expression of SPP2 was associated with worse clinicopathological features like vascular invasion (P=1.6e-05), poor cancer status (with tumor, P=0.021), advanced T stage (T3 or T4, P=4.5e-04), advanced TNM stage (stage III or IV, P=3.1e-04), and with unfavorable prognosis (shorter OS, P=0.002). Gene enrichment analyses revealed that SPP2 might involve in the metabolic homeostasis of HCC and in the development of liver fibrosis and cirrhosis.

Conclusions: SPP2 might inhibit the development of liver fibrosis and cirrhosis and the tumorigenesis of HCC, and analogs of SPP2 might be potential drugs in the prevention of these diseases.