VPS72, a member of VPS protein family, can be used as a new prognostic marker for hepatocellular carcinoma

Abstract

Background: Vacuolar protein sorting (VPS) plays a crucial role in intracellular molecular transport between organelles. However, studies have indicated a correlation between VPSs and tumorigenesis and the development of several cancers. Nevertheless, the association between VPSs and hepatocellular carcinoma (HCC) remains unclear.

Methods: By analyzing databases such as The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC), we investigated the differences in VPSs expression between normal tissue and HCC transcriptomes. Furthermore, we examined the relationship between VPSs expression and overall survival (OS) in patients with HCC. Univariate and multivariate Cox analyses were employed to assess the prognostic value of VPS72 as an independent factor, and the correlation between VPS72 and the tumor immune microenvironment was also analyzed.

Results: We observed significant overexpression of 28 VPSs in HCC tissues compared to normal tissues. The mRNA expression of VPSs displayed a negative correlation with OS, while exhibiting a positive correlation with tumor grade and stage. Additionally, both univariate and multivariate Cox analyses identified VPS72 as a potential independent risk factor for HCC prognosis. Overexpression of VPS72 demonstrated a positive correlation with various clinicopathological factors associated with poor prognosis, as well as the infiltration levels of immune cells.

Conclusion: Therefore, our research shows that VPSs participate in HCC occurrence and development, especially VPS72, which may act as a potential target for HCC treatment and prognosis biomarker.

Keywords: VPS72; bioinformatics; hepatocellular carcinoma; vacuolar protein sorting family.

Figure 1

Transcriptional levels of VPSs family between HCC and normal tissues in TCGA (A) and ICGC (B). *p < .05, **p < .01, and ***p < .001. HCC, hepatocellular carcinoma; ICGC, The International Cancer Genome Consortium; VPS, vacuolar protein sorting; TCGA, The Cancer Genome Atlas.

Figure 2

Analysis of correlation among VPSs, gene mutation, and functional enrichment analysis of VPSs. (A) The mutation rates of VPS13A, VPS13B, VPS13C, and VPS13D are all higher than 10%; missense mutation is the most common mutation type; among the VPS family genes, VPS45 and VPS72 have the highest correlation in TCGA (B) and ICGC (C) databases. (D) The neighbor genes significantly related to VPSs were found through the STRING database. (E) Using Cytoscape 3.7.1 to display PPI results through intergene connectivity, VPS25 and VPS72 played a central role in this network. (F, G) the analysis of annotation, visualization, and comprehensive discovery in the Metascape database. HCC, hepatocellular carcinoma; ICGC, The International Cancer Genome Consortium; PPI, protein–protein interaction; TCGA, The Cancer Genome Atlas; VPS, vacuolar protein sorting.

Figure 3

Prognostic value of different VPSs mRNA expression in hepatocellular carcinoma. (A, B) The mRNA expression level of VPSs was correlated with the OS in patients with HCC. Univariate and multivariate Cox regression analysis of the relationship between VPS72 and clinicopathological factors and OS of patients, The higher expression of VPS72 in patients with death. (E) and higher levels of the pathological stage (F), histologic grade (G), T stage (H), and AFP (L). Significant elevated VPS72 in HCC tissues of patients with postoperative recurrence (I) and vascular infiltration (J), and adjacent hepatic tissue inflammation (K). AFP, alpha‐fetoprotein; HCC, hepatocellular carcinoma; OS, overall survival; VPS, vacuolar protein sorting.

Figure 4

Relationship between VPS72 mRNA level and clinicopathological factors in other databases. (A) VPS72 mRNA level (HCCDB) in different HCC data sets. VPS72 was highly expressed in cancer tissues of HCC patients with multiple data sets in the ONCOMINE database. The fold change was 2.605 (B) in Roessler liver, 2.365 (C) in Roessler liver 2, and 2.342 (D) in Chen liver. The fold change in Wurmbach liver is 2.605 (E); in the Wambach data set, we found that the higher the expression of VPS72 in higher tumor grades (F), HCV positive (G), patients with satellites (H), and vascular invasion (I). HCC, hepatocellular carcinoma.

Figure 5

Volcano map and heat map of VPS72 high and VPS72 low expression in HCC samples. (A) the volcano map is described as 2554 DEGs (| log2fold change| > 1, adjusted p < .05). (B) the histogram of the number of upregulated or downregulated genes. (C, D) in HCC samples with high expression of VPS72 and low expression of VPS72, a heat map showed that 25 significantly upregulated and downregulated genes were correlated with the expression of VPS72. *p < .05, **p < .01, ***p < .001. (E) GSEA enrichment results of VPS72‐related DEGs. DEG, differentially expressed genes; GSEA, Gene Set Enrichment Analysis; HCC, hepatocellular carcinoma; VPS, vacuolar protein sorting.

Figure 6

VPS72 expression and immune cell infiltration were detected by the TIMER database. (A) different proportions of immunocyte subtypes in HCC specimens of the VPS72 high expression group and VPS72 low expression group. (B, C) The correlation between the expression of VPS72 and 24 immune infiltrating cells. *p < .05, **p < .01, ***p < .001. HCC, hepatocellular carcinoma; VPS, vacuolar protein sorting.