To analyze the relationship between the expression level of hyaluronan and proteoglycan link protein 1 (HAPLN1) and the prognosis of hepatocellular carcinoma (HCC) patients, and to investigate its correlation with immune cell infiltration of HCC.

Based on the TCGA database, the expression of HAPLN1 in HCC and its relationship with clinicopathological features and prognosis were analyzed. The risk factors of prognosis of HCC were screened by univariate and multivariate Cox’s regression analyses. The nomogram model was constructed to quantitatively analyze the survival and prognosis. ROC curve was delineated to evaluate the predictive value of HAPLN1 for clinical prognosis of HCC patients. The pathway and cell function of differentially-expressed genes between the high and low HAPLN1 expression groups were subject to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses using Cluster Profile software package for HAPLN1-related pathways were visualized by using Gene Set Enrichment Analysis (GSEA). The correlation between HAPLN1 and 24 types of immune cells in HCC was analyzed by CIBERSORT core algorithm. The enrichment of 24 types of immune cells in HCC in high and low HAPLN1 expression groups was assessed by ssGSEA algorithm. The correlation between immune checkpoints and HAPLN1 in HCC was further investigated.

TCGA database analysis showed that the expression level of HAPLN1 was up-regulated in HCC tissues, significantly higher than that in matched normal liver tissues (P=0.002). HCC patients with high expression of HAPLN1 had shorter overall survival (HR=1.560, 95%CI: 1.100-2.218, P=0.013). HAPLN1 expression was significantly correlated with T stage, vascular invasion and pathological stage (χ²=9.149, 9.518, 6.614; all P<0.05). Multivariate Cox’s regression analysis showed that T stage (HR=2.622, 95%CI: 1.692-4.062; P<0.05) and HAPLN1 expression (HR=1.622, 95%CI: 1.072~2.585; P=0.023) were the independent risk factors for clinical prognosis of HCC patients. Prognostic nomogram analysis revealed that HAPLN1 had high predictive value for clinical prognosis of HCC (AUC=0.737, 95%CI: 0.685-0.788). GO and KEGG enrichment analyses showed that the differentially-expressed genes of HAPLN1 were mainly enriched in the functional pathways such as apical plasma membrane, signal receptor activation and signal ligand activity and bile secretion, etc. Immune cell correlation analysis showed that HAPLN1 was closely associated with multiple immune cells in HCC, and was positively correlated with immune checkpoints.

HCC patients with high expression of HAPLN1 have poor prognosis. The nomogram model based on the expression of HAPLN1 combined with pathological TNM staging provides effective reference for predicting clinical prognosis of HCC patients. HAPLN1 may promote the progression of HCC through regulating tumor immune microenvironment.