Prognostic significance of chemokines CCL11 and CCL5 modulated by low-density lipoprotein cholesterol in colon cancer patients with normal body mass index

Abstract

Background: Many studies have shown an elevated level of cholesterol in colon tumors as compared to normal tissue. Obesity and high low-density lipoprotein cholesterol (LDL-C) are known risk factors for colon cancer. However, the role of LDL-C in colon cancer patients with normal body mass index (BMI) remains elusive.Methods: Levels of serum cholesterol and oxysterols were quantified by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) from 129 individuals with normal BMI, including 32 with solitary polyp, 36 with multiple polyps, and 31 with adenocarcinoma as well as 32 healthy controls. In vitro, colon cancer cells were treated with LDL-C and assayed for chemokines via RNA-Seq and mitochondrial morphology via transmission electron microscopy and immunofluorescence. Additionally, correlation analysis was performed between LDL-C-induced chemokines and the overall survival of colon cancer patients from the Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx), and the Human Protein Atlas (HPA) database. Results:The serum cholesterol level was significantly higher in colon adenocarcinoma patients with normal BMI than that in healthy controls (P<0.001). LDL-C potentiated colon cancer cell invasion and resistance to glucose-deprivation in vitro via chemokine-mediated signaling, mainly upregulation of CC chemokine ligand (CCL) 5 and downregulation of CCL 11. By analyzing the RNA expression data of colorectal cancer from TCGA, GTEx, and HPA, we demonstrated that the CCL5 level in colorectal adenocarcinoma tissues was significantly increased relative to adjacent normal tissues (P=0.01) while the CCL11 level was decreased (P=0.01). Both increased CCL5 and decreased CCL11 showed a negative correlation with the 5-year overall survival in tumor node metastasis (TNM) stage II colon cancer patients (P=0.0032, 0.026 for CCL5 and CCL11, respectively). Conclusions:Our study supports the idea that LDL-C regulates the expression of CCL5 and CCL11 chemokines, which may have predictive values for survival in colon cancer patients with normal BMI, especially for patients in TNM stage II.

Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes

“…Other factors including calprotectin, a sensitive marker for mucosal inflammation of the intestine [ 50 ] or lactoferrin, a first-line defense protein for protection against microbial infections [ 51 ] were increased in our patients with obesity and T2D. Reportedly, pro-inflammatory chemokines exhibit important roles in the development of intestinal diseases even in colon carcinogenesis [ 52 , 53 ]. An aberrant microbiota has been shown to induce the epithelial expression of CCL5, promoting a spontaneous and exaggerated autoinflammatory response [ 28 ].…”

The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium

“…As a consequence, the increased plasma LDL-C levels could cause hypercholesterolemia that is associated with tumor cell growth 37 . It has been reported that LDL-C could potentiate colon cancer cell resistance to glucose-deprivation 38 . In our study, we found that recombinant Pcsk9 protein could decrease the protein level of Ldlr (Supplementary Fig.…”

Deciphering the Pyroptosis-Related Prognostic Signature and Immune Cell Infiltration Characteristics of Colon Cancer

“…Our results showed that CTLA4 expression is related to the tumor infiltration characteristics of multiple immune cell types. CCL11, a neutrophil-related chemokine, exerts a chemotactic effect on eosinophils by interacting with CXCR3 and CCR5 ( Wang et al, 2021b ), which was found to be a potential prognostic signature for TNM stage II CC patients ( Liu et al, 2021b ). NIN is essential for the construction of the centrosome and helps regulate cell migration and polarity ( Goldspink et al, 2017 ).…”