LCAT in Cancer Biology: Embracing Epigenetic Regulation, Immune Interactions, and Therapeutic Implications

Abstract

Lecithin cholesterol acyltransferase (LCAT) is a crucial enzyme in high-density lipoprotein (HDL) metabolism that is often dysregulated in cancers, affecting tumor growth and therapy response. We extensively studied LCAT expression in various malignancies, linking it to clinical outcomes and genetic/epigenetic alterations. We analyzed LCAT expression in multiple cancers and used the Cox regression model to correlate it with patient survival metrics, including overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). We also examined the copy number variations (CNVs), single-nucleotide variations (SNVs), DNA methylation, and N6-methyladenosine (m6A) modifications of LCAT and their connections to tumor immune responses and drug sensitivity. LCAT expression varies among cancers and correlates with patient outcomes. Low expression is linked to poor prognosis in low-grade glioma (LGG) and liver hepatocellular carcinoma (LIHC), while high expression is associated with better outcomes in adrenocortical carcinoma (ACC) and colon adenocarcinoma (COAD). In kidney renal papillary cell carcinoma (KIRP) and uterine corpus endometrial carcinoma (UCEC), LCAT CNV and methylation levels are prognostic markers. LCAT interacts with m6A modifiers and immune molecules, suggesting a role in immune evasion and as a biomarker for immunotherapy response. LCAT expression correlates with chemotherapeutic drug IC50 values, indicating potential for predicting treatment response. In ACC and COAD, LCAT may promote tumor growth, while in LGG and LIHC, it may inhibit progression. LCAT expression and activity regulation could be a new cancer therapy target. As a key molecule linking lipid metabolism, immune modulation, and tumor progression, the potential of LCAT in cancer therapy is significant. Our findings provide new insights into the role of LCAT in cancer biology and support the development of personalized treatment strategies.

Keywords: HDL; LCAT; cancer metabolism; epigenetic alterations; immune modulation; personalized cancer therapy.

Figure 1

Differential expression analysis of LCAT in various tissues. (A). Expression of LCAT in normal tissues. (B). Expression of LCAT across TCGA tumors. (C). Differential expression of LCAT between normal and tumor tissues. (D). Differential expression of LCAT between tumor tissues and paired adjacent normal tissues. * p < 0.05; ** p < 0.01; *** p < 0.001; ^ns p < 0.05.

Figure 2

Expression of LCAT in tumor tissue samples and cells. (A). Representative immunohistochemical images of LCAT expression in tumor tissue samples (two images for each cancer type). (B). Immunofluorescence images of LCAT in cervical cancer cell line (A431), osteosarcoma cell line (U20S), and glioblastoma cell line (U-251MG). LCAT is marked with green fluorescence, microtubules with red fluorescence, and cell nuclei with blue DAPI staining.

Figure 3

Relationship between LCAT expression and overall survival (OS) and disease-specific survival (DSS) in 33 cancer types from the TCGA database. (A) Kaplan-Meier survival curves for the relationship between LCAT expression and OS in ACC, COAD, KICH, KIRC, LGG, LIHC, MESO, and THYM tumors (p < 0.05). (B) Kaplan-Meier survival curves for the relationship between LCAT expression and DSS in ACC, COAD, LGG, and LIHC tumors (p < 0.05). * p < 0.05.

Figure 4

Relationship between LCAT expression and overall survival (OS) and progression-free interval (PFI) in 33 cancer types from the TCGA database. Kaplan-Meier survival curves for the relationship between LCAT expression and PFI in ACC, COAD, KICH, LGG, LIHC, and THYM tumors (p < 0.05). * p < 0.05.

Figure 5

CNV summary and its correlation with LCAT expression and survival rates in different types of tumors. (A) Pie chart summary of the proportion of different LCAT CNVs in 33 cancer types. (B) Scatter plot of Spearman correlation between LCAT CNV and mRNA expression in various cancer types. (C) Survival analysis of LCAT CNV in KIRP (OS, PFS, DSS, and DFI). (D) Survival analysis of LCAT CNV in UCEC (OS, PFS, DSS, and DFI).

Figure 6

SNV summary and its correlation with LCAT expression and survival rates in different types of tumors. (A) Lollipop plot showing mutation sites, types, and counts of LCAT in selected cancer-type sample sets. (B) Number of harmful variations in tumor samples of selected cancer types. (C) Count of SNPs and DELs in the input gene set of selected cancer types. (D) Count of each SNV category in the input gene set of selected cancer types. (E) Bubble chart showing the survival differences between LCAT mutants and wild types in different tumor patients. (F) Heatmap showing the correlation between LCAT expression and MRR genes in different tumor types. * p < 0.05.

Figure 7

Methylation analysis of LCAT expression in different tumor types. (A) Methylation differences of LCAT between tumor and normal samples in different cancer types. (B) Correlation analysis between LCAT methylation and mRNA expression in 33 tumors. (C) Survival analysis of high and low methylation groups in LGG, LIHC, SARC, and UVM. (D) Correlation analysis between LCAT expression and DNA methyltransferases in different tumor types. * p < 0.05; **** p < 0.0001.

Figure 8

M6A Modification Analysis Related to LCAT. (A) Heatmap of the correlation analysis between LCAT expression and m6A regulatory factors in different tumor types. (B,C) Expression of LCAT in m6A regulator mutant and wild types in different cancer types (all p < 0.05). (D) Identification chart of m6A modification sites in the LCAT mRNA sequence. * p < 0.05.

Figure 9

Correlation analysis between LCAT expression and immune infiltration in 33 tumor types. (A) Bar chart showing the enrichment scores of immune cells in LCAT high expression and low expression groups in different types of tumor samples. (B) Distribution of multiple immune cell scores in LCAT high and low expression groups in selected tumors. * p < 0.05; ** p < 0.01; *** p < 0.001.

Figure 10

Correlation analysis of LCAT expression with immune-related genes across 33 tumor types. Correlation analysis of LCAT expression with immune checkpoints (A), MHC molecules (B), immune suppressors (C) and immune stimulatory factors (D) in 33 tumor types. * p < 0.05.

Figure 11

Correlation between LCAT expression and TMB and MSI. (A) Lollipop plot of the correlation between LCAT expression and TMB in pan-cancer. (B) Lollipop plot of the correlation between LCAT expression and MSI in pan-cancer.

Figure 12

Correlation Analysis of LCAT expression and drug sensitivity. (A) Correlation analysis of LCAT expression with CTRP drug sensitivity (top 30). (B) Correlation analysis of LCAT gene expression with GDSC drug sensitivity.

Figure 13

Functional enrichment analysis of LCAT affecting the progression of ACC, COAD, LGG, and LIHC tumors. Mountain plots showing GSEA analysis of LCAT high and low expression groups in ACC (A), COAD (B), LGG (C), and LIHC (D) tumors. Mountain plots showing Reactome analysis of LCAT high and low expression groups in ACC (E), COAD (F), LGG (G), and LIHC (H) tumors.