Comprehensive Analysis of LPCATs Highlights the Prognostic and Immunological Values of LPCAT1/4 in Hepatocellular Carcinoma

Abstract

Background: The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains poor. Lipid remodeling modulators are considered promising therapeutic targets of cancers, owing to their functions of facilitating cancer cells' adaption to the limited environment. Lysophosphatidylcholine acyltransferases (LPCATs) are enzymes regulating bio-membrane remodeling, whose roles in HCC have not been fully illuminated.

Methods: Multiple bioinformatic tools were applied to comprehensively evaluate the expression, genetic alterations, clinical relevance, prognostic values, DNA methylation, biological functions, and correlations with immune infiltration of LPCATs in HCC.

Results: We found LPCAT1 was significantly overexpressed and the most frequently altered in HCC. The high-expression of LPCAT1/4 indicated clinicopathological advancements and poor prognoses of HCC patients. Even though the global DNA methylation of LPCATs in HCC showed no significant difference with that in normal liver, the hypermethylation of numerous CpG sites of them implied worse survivals of HCC patients. Thirty LPCATs' interactive genes were identified, which were generally membrane components and partook in phospholipid metabolism pathways. Finally, we found the expression of LPCATs was extensively positively correlated with the infiltration of various stimulatory and suppressive tumor-infiltrating immune cells (TIICs) in the tumor microenvironment.

Conclusion: This study addressed LPCAT1/4 were potential prognostic and immunotherapeutic biomarkers of HCC targeting bio-membrane lipid remodeling.

Keywords: LPCATs; bioinformatics; biomarker; hepatocellular carcinoma; immune infiltration.

Figure 1

The mRNA expression of LPCATs in HCC and normal liver tissues. (A) A summary of the datasets in which LPCATs were significantly up- (red) or down- (blue) expressed in various cancers, compared with the corresponding normal liver tissues (Oncomine). Numbers in colored cells represent the counts of datasets. The color of cells is paralleled with the best gene rank percentile for the analyses within the cell. (B) The mRNA expression of LPCATs in HCC and normal liver samples (GEPIA2). *P < 0.05.

Figure 2

Genetic alterations of LPCATs in HCC. (A) An overview of the genetic alterations of LPCATs occurring in HCC samples. (B and C) The impacts of the overall genetic alteration of LPCATs on (B) OS and (C) DFS of HCC patients (cBioPortal).

Figure 3

Associations between LPCATs expression and distinct clinicopathological features of HCC patients. The expression of LPCAT1-4 in HCC patients with diverse (A–D) pathological stages and (E–H) tumor grades (UALCAN). *P < 0.05, **P < 0.01, ***P < 0.001. The expression of (I) LPCAT1 and (J) LPCAT4 in HCC patients in different pathologic T stages (LinkedOmics).

Figure 4

Prognostic significance of LPCATs in HCC patients. Associations between LPCATs expression with (A) OS, (B) RFS, (C) PFS, and (D) DSS of HCC patients (KM plotter).

Figure 5

Prognostic significance of the methylated CpG sites of LPCATs on OS of HCC patients (MethSurv).

Figure 6

Underlying functional mechanisms of LPCATs and their interactive genes. (A) Thirty interactive genes of LPCATs identified by GeneMANIA. In the network, nodes represent genes, edges represent interactions between any two genes, and edge colors represent interaction types. (B) The PPI network constructed using LPCATs and their interactive genes by STRING. Edge thicknesses indicate confidence strengths. (C) The five core genes in the PPI network. The redder the color of a node, the higher the degree value is. (D) Correlations among LPCATs and the five core genes. The significantly enriched (E) GO-BP, (F) GO-CC, (G) GO-MF, and (H) KEGG pathway terms for LPCATs and their interactive genes.

Figure 7

Correlations between LPCATs expression and immune infiltration of HCC. (A) Correlations between LPCATs expression with tumor purity, and infiltration levels of CD8+ T cells, CD4+ T cells, mDCs, neutrophils, macrophages, B cells, Tregs, and MDSCs in the TME of HCC (TIMER). (B) Correlations between LPCATs and the expression of biomarkers of Th cells and TAMs in HCC. Red or blue color represents positive or negative correlation, respectively. Correlation coefficients with statistical significance are in bold.