Transcriptomic Data Analyses Reveal a Reprogramed Lipid Metabolism in HCV-Derived Hepatocellular Cancer

Abstract

Reprograming lipid metabolism, one of the major metabolic alterations in cancer, is believed to play an essential role in cancer development, but the exact molecular mechanism remains elusive. Here, we present a computational study of transcriptomic data of HCC with HCV etiology to investigate how lipid metabolism alters during HCC progression. Our analyses reveal that: (1) cancer tissue cells tend to synthesize fatty acids de novo and its phospholipid derivatives; (2) lipid catabolism and fatty acid oxidation are remarkably down-regulated in HCC; (3) the lipid metabolism in HCC is largely independent of lipids in blood circulation; (4) stage-specific co-expression networks for lipid metabolic genes were identified during HCC progression; and (5) the expression levels of several lipid metabolic genes that are differentially expressed or co-expressed specifically at the HCC stage have a strong correlation with cancer survival. Overall, the results provide detailed information about the reprogramed lipid metabolism in HCV-derived HCC.

Keywords: de novo synthesis of fatty acid; gene co-expression; gene set enrichment; hepatocellular cancer; lipid metabolism.

FIGURE 1

Venn diagrams for the DEGs in cirrhotic, dysplastic, and HCC samples. (A) Up-regulated genes. (B) Down-regulated genes. (C) Up-regulated lipid metabolic genes. (D) Down-regulated lipid metabolic genes.

FIGURE 2

A heat-map for the differentially expressed lipid metabolic genes. Rows and columns represent genes and samples, respectively, and gene names are given in Supplementary Table S1. Expression values of each gene were centralized at the mean of normal samples and divided by the standard deviation of all samples.

FIGURE 3

Representative GO terms enriched by the DEGs in cirrhotic (A), dysplastic (B), and HCC samples (C). A term marked as “up” indicates that it is activated, and “down” represents that it is repressed. The list of enriched GO terms is given in Supplementary Table S2.

FIGURE 4

The deviation of LMGs from controls in their expression (| logFC|) has weak positive correlations (Pearson correlation) with the connectivity of LMGs.

FIGURE 5

Heat-maps for stage-specific co-expression networks of lipid metabolic genes. (A) Cirrhotic-specific co-expression. (B) Dysplastic-specific co-expression. (C) HCC-specific co-expression. The Pearson’s correlation coefficients are color-coded as depicted in the sidebar. The co-expressed gene-pairs in the heat-maps are provided in Supplementary Table S3.

FIGURE 6

GO terms enriched by the genes co-expressed with LMGs in the stage-specific networks. Enriched GO terms for dysplastic-specific network (A) and HCC-specific network (B). No GO terms were enriched for cirrhotic samples. The top 20 biological process-associated GO terms with small adjusted p-values are shown.

FIGURE 7

Correlations between survival rates and the expression levels of HCC-specific or consistently regulated LMGs (shown in bold in Table 2).

FIGURE 8

Expression levels of key LMGs in HCV-derived HCC. (A) A heat-map for these genes in HCC vs. controls (GSE6764), where the displayed numbers are logFC values. Only the DEGs with adjusted p-value <0.01 are shown, and the full list of genes analyzed here is given in Supplementary Table S1. ACSL4 is categorized into a lipid synthesis group according to its role found in (Doll et al., 2017); (B) A schematic depiction of the reprogramed lipid metabolism in HCC. Different colors are used to mark differential expressions: pink, blue, and green represent up-regulation, down-regulation, and no significant changes, respectively. The results of differential expression analysis and GO enrichment analysis suggest increased de novo synthesis of fatty acids, reduced lipid exchange between HCC tumor and its environment, and down-regulated lipid catabolic process and fatty acid oxidation in HCC.