Reduced serum high-density lipoprotein cholesterol levels and aberrantly expressed cholesterol metabolism genes in colorectal cancer

Abstract

Background: Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract. Lipid metabolism, as an important part of material and energy circulation, is well known to play a crucial role in CRC.

Aim: To explore the relationship between serum lipids and CRC development and identify aberrantly expressed cholesterol metabolism genes in CRC.

Methods: We retrospectively collected 843 patients who had confirmed CRC and received surgical resection from 2013 to 2015 at the Cancer Hospital of the Chinese Academy of Medical Sciences as our research subjects. The levels of serum total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C and clinical features were collected and statistically analyzed by SPSS. Then, we used the data from Oncomine to screen the differentially expressed genes (DEGs) of the cholesterol metabolism pathway in CRC and used Gene Expression Profiling Interactive Analysis to confirm the candidate DEGs. PrognoScan was used to analyze the prognostic value of the DEGs, and Search Tool for the Retrieval of Interacting Genes was used to construct the protein-protein interaction network of DEGs.

Results: The serum HDL-C level in CRC patients was significantly correlated with tumor size, and patients whose tumor size was more than 5 cm had a lower serum HDL-C level (1.18 ± 0.41 mmol/L vs 1.25 ± 0.35 mmol/L, P < 0.01) than their counterparts. In addition, TC/HDL (4.19 ± 1.33 vs 3.93 ± 1.26, P < 0.01) and LDL-C/HDL-C (2.83 ± 1.10 vs 2.61 ± 0.96, P < 0.01) were higher in patients with larger tumors. The levels of HDL-C (P < 0.05), TC/HDL-C (P < 0.01) and LDL-C/HDL-C (P < 0.05) varied in different stages of CRC patients, and the differences were significant. We screened 14 differentially expressed genes (DEGs) of the cholesterol metabolism pathway in CRC and confirmed that lipoprotein receptor-related protein 8 (LRP8), PCSK9, low-density lipoprotein receptor (LDLR), MBTPS2 and FDXR are upregulated, while ABCA1 and OSBPL1A are downregulated in cancer tissue. Higher expression of LDLR (HR = 3.12, 95%CI: 1.77-5.49, P < 0.001), ABCA1 (HR = 1.66, 95%CI: 1.11-2.48, P = 0.012) and OSBPL1A (HR = 1.38, 95%CI: 1.01-1.89, P = 0.041) all yielded significantly poorer DFS outcomes. Higher expression of FDXR (HR = 0.7, 95%CI: 0.47-1.05, P = 0.002) was correlated with longer DFS. LDLR, ABCA1, OSBPL1A and FDXR were involved in many important cellular function pathways.

Conclusion: Serum HDL-C levels are associated with tumor size and stage in CRC patients. LRP8, PCSK9, LDLR, MBTPS2 and FDXR are upregulated, while ABCA1 and OSBPL1A are downregulated in CRC. Among them, LDLR, ABCA1, OSBPL1A and FDXR were valuable prognostic factors of DFS and were involved in important cellular function pathways.

Keywords: Cholesterol metabolism; Colorectal cancer; High-density lipoprotein cholesterol; Prognosis.

Figure 1

Comparison of concept: “Cholesterol metabolism - go biological process” in skrzypczak colorectal. A: Upregulated expression of genes in the cholesterol metabolism pathway of colorectal cancer (CRC); B: Downregulated expression of genes in the cholesterol metabolism pathway of CRC.

Figure 2

Identification of candidate differentially expressed genes. The mRNA expression of differentially expressed genes between tumor and normal tissues was plotted by Gene Expression Profiling Interactive Analysis (GEPIA) with data from the The Cancer Genome Atlas database. A-C: Lipoprotein receptor-related protein 8, PCSK9, and low-density lipoprotein receptor (LDLR) were upregulated in colorectal cancer tissue compared with normal tissue; D, E: MBTPS2 and FDXR showed significantly higher expression only in rectal cancer and colon cancer, respectively; F, G: ABCA1 and OSBPL1A were downregulated in CRC tissue, consistent with the results from Oncomine; H: CELA3A was downregulated; I: SORL1 was upregulated in cancer tissue, which is the reverse of the above results; J-N: The expression levels of APOL1, VLDLR, HDLBP, SREBF2 and APOL2 were comparable between cancer and normal tissues according to the GEPIA analysis results.

Figure 3

Correlation of differentially expressed gene expression and disease-free survival in patients with colorectal cancer. The survival curves comparing the patients with high (red) and low (blue) expression were plotted from the PrognoScan database. A-C: High mRNA expression of low-density lipoprotein receptor, ABCA1 and OSBPL1A was an unfavorable prognostic factor for disease-free survival (DFS) in colorectal cancer (CRC) patients; D: High mRNA expression of FDXR was a favorable prognostic factor for DFS in CRC patients; E-G: Lipoprotein receptor-related protein 8, PCSK9 and MBTPS2 expression could not be used to predict DFS outcome according to the results of this analysis.

Figure 4

Protein–protein interaction network of differentially expressed genes with prognostic value. Interacting nodes are displayed in colored circles using Search Tool for the Retrieval of Interacting Genes v10.0. A: Low-density lipoprotein receptor only involved in cholesterol metabolism pathway; B: FDXR was also involved in xenobiotic metabolic processes, cellular responses to xenobiotic stimuli and oxidation–reduction processes; C: ABCA1 was shown to be involved in the steroid hormone-mediated signaling pathway; D: OSBPL1A was involved in antigen processing and presentation of exogenous peptide antigens via MHC class II, microtubule-based movement and vesicle-mediated transport.