Immune infiltration-associated serum amyloid A1 predicts favorable prognosis for hepatocellular carcinoma.

backgroundSerum amyloid A1 (SAA1) is an acute-phase protein involved in acute or chronic hepatitis. Its function is still controversial. In addition, the effect of the expression of SAA1 and its molecular function on the progression in hepatocellular carcinoma (HCC) is still unclear.

aimTo demonstrate the expression of SAA1 and its effect on the prognosis in HCC and explain further the correlation of SAA1 and immunity pathways.

methodsSAA1 expression in HCC was conducted with The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) in GEPIA tool, and the survival analysis based on the SAA1 expression level was achieved in the Kaplan-Meier portal. The high or low expression group was then drawn based on the median level of SAA1 expression. The correlation of SAA1 and the clinical features were conducted in the UALCAN web-based portal with TCGA-LIHC, including tumor grade, patient disease stage, and the TP53 mutation. The correlation analysis between SAA1 expression and TP53 mutation was subjected to the TCGA portal. The tumor purity score and the immune score were analyzed with CIBERSORT. The correlation of SAA1 expression and tumor-infiltrating lymphocytes was achieved in TISIDB web-based integrated repository portal for tumor-immune system interactions. GSE125336 dataset was used to test the SAA1 expression in the responsive or resistant group with anti-PD1 therapy. Gene set enrichment analysis was applied to evaluate the gene enrichment signaling pathway in HCC. The similar genes of SAA1 in HCC were identified in GEPIA, and the protein-protein interaction of SAA1 was conducted in the Metascape tool. The expression of C-X-C motif chemokine ligand 2, C-C motif chemokine ligand 23, and complement C5a receptor 1 was studied and overall survival analysis in HCC was conducted in GEPIA and Kaplan-Meier portal, respectively.

resultsSAA1 expression was decreased in HCC, and lower SAA1 expression predicted poorer overall survival, progression-free survival, and disease-specific survival. Furthermore, SAA1 expression was further decreased with increased tumor grade and patient disease stage. Also, SAA1 expression was further downregulated in patients with TP53 mutation compared with patients with wild type TP53. SAA1 expression was negatively correlated with the TP53 mutation. Lower SAA1 predicted poorer survival rate, especially in the patients with no hepatitis virus infection, other than those with hepatitis virus infection. Moreover, the SAA1 expression was negatively correlated with tumor purity. In contrast, SAA1 expression was positively correlated with the immune score in HCC, and the correlation analysis between SAA1 expression and tumor-infiltrating lymphocytes also showed a positive correlation in HCC. Decreased SAA1 was closely associated with the immune tolerance of HCC. C-X-C motif chemokine ligand 2 and C-C motif chemokine ligand 23 genes were identified as the hub genes associated with SAA1, which could also serve as favorable prognosis markers for HCC.

conclusionSAA1 is downregulated in the liver tumor, and it is closely involved in the progression of HCC. Lower SAA1 expression indicates lower survival rate, especially for those patients without hepatitis virus infection. Lower SAA1 expression also suggests lower immune infiltrating cells, especially for those with immune cells exerting anti-tumor immune function. SAA1 expression is closely associated with the anti-tumor immune pathways.