Published online May 16, 2022. doi: 10.12998/wjcc.v10.i14.4446
Peer-review started: March 8, 2022
First decision: March 24, 2022
Revised: March 27, 2022
Accepted: April 20, 2022
Article in press: April 20, 2022
Published online: May 16, 2022
Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract. It ranks third in the incidence of male malignant tumors in the world and second in female malignant tumors. The occurrence and development of CRC involve multiple dysregulated genes and complicated physiological processes. Lipid metabolism, as an important part of material and energy circulation, is well known to play a crucial role in CRC. Numerous studies have found that lipid abnormalities are closely related to CRC. Most of these studies focus on the different lipid levels between healthy people and patients with CRC, but it is difficult to clarify the specific causal relationship between lipid alterations and cancer. Additionally, research on the underlying mechanism is relatively scarce.
In previous studies, we found that CRC is closely related to serum cholesterol levels, but the specific key genes that affect the occurrence, development and prognosis of CRC are unknown. The aim of this study was to explore more evidence for altered cholesterol metabolism and to identify potential cancer-related metabolic genes in CRC.
The objective is to explore the relationship between serum lipids and CRC development and identify aberrantly expressed cholesterol metabolism genes in CRC.
We reviewed 843 CRC patients and collected serum total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL- Statistical analysis of C levels and clinical characteristics was performed by SPSS. Meanwhile, we screened the differentially expressed genes (DEGs) of cholesterol metabolism pathways in CRC using the database data of Oncomine, and confirmed candidate DEGs using GEPIA. PrognoScan was used to analyze the prognostic value of DEGs, and Search Tool for the Retrieval of Interacting Genes was used to construct the protein–protein interaction network of DEGs to finally understand the relationship between CRC and cholesterol metabolism.
Serum HDL-C levels in CRC patients were significantly correlated with tumor size, and serum HDL-C levels were lower in patients with tumors larger than 5 cm, on the contrary, TC/HDL [4.19 ± 1.33 vs HDL-C (2.83 ± 1.10 vs 2.61 ± 0.96, P < 0.01)] was higher. There were significant differences in the levels of HDL-C (P < 0.05), TC/HDL-C (P < 0.01) and LDL-C/HDL-C (P < 0.05) in CRC patients of different stages, and the differences were statistically significant. The authors screened 14 differentially expressed genes (DEGs) with the most significant cholesterol metabolic pathways in CRC and confirmed that lipoprotein receptor-related protein 8 (LRP8), PCSK9, low-density lipoprotein receptor (LDLR), MBTPS2 and FDXR were up-regulated in cancer tissues, while ABCA1 and OSBPL1A were down-regulated. 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)) in cancer tissue high expression of all produced significantly poorer DFS results. Higher expression of FDXR (HR = 0.7, 95%CI: 0.47-1.05, P = 0.002) was associated with longer DFS. LDLR, ABCA1, OSBPL1A, and FDXR are also involved in many other important cellular functional pathways.
Serum HDL-C levels are closely related to tumor size and stage in CRC patients. In CRC, LRP8, PCSK9, LDLR, MBTPS2, and FDXR genes were up-regulated, while ABCA1 and OSBPL1A genes were down-regulated. Meanwhile, LDLR, ABCA1, OSBPL1A and FDXR genes are valuable prognostic factors for DFS and participate in other important functional pathways of cells.
Only a few metabolic genes are presently known to be directly implicated in CRC, especially in the cholesterol metabolism pathway, and there is still much more to learn about the causal role of metabolic genes in CRC. By studying the mechanism of key genes in the cholesterol metabolism pathway in CRC, more treatment options for CRC can be provided.