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

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.