Association of Adiponectin Receptors with Metabolic and Immune Homeostasis Parameters in Colorectal Cancer: In Silico Analysis and Observational Findings.

Adiponectin (ADIPOQ) as both a regulator of metabolic homeostasis and a protein involved in immune response might be of particular interest to contemporary laboratory medicine, especially in terms of minimally invasive diagnostics. The diverse roles of ADIPOQ with regard to the immune and metabolic aspects of colorectal carcinogenesis have been proposed. However, the expression of its receptors ADIPOR1 and ADIPOR2 is scarcely explored in peripheral blood mononuclear cells (PBMCs). Moreover, ADIPORs' relationships with the immune response mediator TNF-α have not been previously investigated in the PBMCs of CRC patients. This study used both in silico and observational case-control analyses with the aim of exploring the association of ADIPOR gene expression and ADIPOQ single nucleotide polymorphisms (SNPs) with the inflammatory marker TNF-α and lipid status parameters in patients with CRC. Publicly available transcriptomic datasets (GSE47756, GSE44076) obtained from analyses of monocytes and CRC tissue samples were employed for the in silico evaluation of ADIPORs' specific genetic traits. GSE47756 and GSE44076 datasets were processed with GSEA software to provide a genetic fingertip of different signaling pathways associated with ADIPORs' mRNA levels. The case-control aspect of the study included the PBMC samples of 73 patients diagnosed with CRC and 80 healthy volunteers. The PCR method was carried out for the PBMC gene expression analysis (ADIPOR1, ADIPOR2, TNF-α mRNA levels) and for the subjects' genotyping (ADIPOQ rs266729, ADIPOR1 rs7539542). GSEA showed significant associations of ADIPOR mRNA expression with gene sets related to metabolic and immune homeostasis in both datasets. The case-control study revealed the association of ADIPOR1 rs7539542 with reduced lipid status parameters in CRC. In addition, PBMC ADIPOR1 mRNA levels decreased in CRC (p < 0.001), whereas ADIPOR2 mRNA did not differ between the groups (p = 0.442). A reduction in PBMC TNF-α mRNA levels was noted in CRC (p < 0.05). Our results indicate that ADIPOR1 and ADIPOR2 play a significant role in the alteration of both metabolic and immune homeostasis during the progression of CRC. For the first time, ADIPOR1 is shown to be a specific receptor for mediating ADIPOQ's effects in the PBMCs of CRC patients.

Can non-cholesterol sterols indicate the presence of specific dysregulation of cholesterol metabolism in patients with colorectal cancer?

Colorectal cancer (CRC) is a highly prevalent malignancy. Previous studies suggested that cholesterol might play a signficant role in malignant transformation and proliferation. Non-cholesterol sterols (NCS), which are transported by serum lipoproteins alongside cholesterol, are regarded as cholesterol synthesis and absorption markers. Quantification of NCS in serum and HDL fraction (NCSHDL), could provide a better insight into the cholesterol metabolism. The aim of this study was to examine the status of cholesterol synthesis and cholesterol absorption markers in serum and HDL fraction and explore their interrelation in CRC patients. Current study was designed as observational, case-control study. The study included 73 CRC patients and 95 healthy subjects. NCS and NCSHDL concentrations were determined by HPLC-MS/MS. Based on NCS and NCSHDL concentrations, different cholesterol homeostasis indices were calculated. Patients had significantly lower NCS (P<0.001) and NCSHDL concentrations (P<0.001 for desmosterolHDL; P<0.05 for lathosterolHDL, P=0.001 for campesterolHDL, P<0.001 for ß-sitosterolHDL). NCSHDL/NCS (P<0.005 for desmosterolHDL/desmosterol; P<0.05 for lathosterolHDL/lathosterol; P<0.001 for both ß-sitosterolHDL/ß-sitosterol and campesterolHDL/campesterol) and synthesis to absorption ratio (CSI/CAI) (P<0.005) were increased in CRC patients. Additionally, low serum concentrations of desmosterol (P<0.001; OR=0.329; 95%CI (0.199-0.542)) and campesterol (P<0.001; OR=0.540; 95%CI (0.424-0.687)) were independent predictors of CRC presence. Our data suggest that cholesterol homeostasis in CRC is shifted towards increased synthesis. Relative abundance of NCS in HDL particles is increased, suggesting the possible overproduction of cholesterol precursors in peripheral tissues.

Revealing the Role of High-Density Lipoprotein in Colorectal Cancer.

Colorectal cancer (CRC) is a highly prevalent malignancy with multifactorial etiology, which includes metabolic alterations as contributors to disease development. Studies have shown that lipid status disorders are involved in colorectal carcinogenesis. In line with this, previous studies have also suggested that the serum high-density lipoprotein cholesterol (HDL-C) level decreases in patients with CRC, but more recently, the focus of investigations has shifted toward the exploration of qualitative properties of HDL in this malignancy. Herein, a comprehensive overview of available evidences regarding the putative role of HDL in CRC will be presented. We will analyze existing findings regarding alterations of HDL-C levels but also HDL particle structure and distribution in CRC. In addition, changes in HDL functionality in this malignancy will be discussed. Moreover, we will focus on the genetic regulation of HDL metabolism, as well as the involvement of HDL in disturbances of cholesterol trafficking in CRC. Finally, possible therapeutic implications related to HDL will be presented. Given the available evidence, future studies are needed to resolve all raised issues concerning the suggested protective role of HDL in CRC, its presumed function as a biomarker, and eventual therapeutic approaches based on HDL.

Associations of cholesterol and vitamin D metabolites with the risk for development of high grade colorectal cancer.

BACKGROUND: Vitamin D deficiency is repeatedly reported in colorectal cancer (CRC). Since cholesterol and vitamin D share common precursor 7-dehydrocholesterol (7-DHC), it would be important to explore the associations of key vitamin D metabolites and serum lipid parameters in patients with high and low grade CRC. The aim of this study was to analyze relationships between serum 25(OH)D3, 24,25(OH)2D3 and 7-DHC levels and serum lipids in patients with CRC, and to evaluate their potential for prediction of risk for development of high grade CRC. METHODS: We recruited 82 patients CRC and 77 controls. 7-DHC, 25(OH)D3 and 24,25(OH)2D3 were quantified by LC-MS/MS methods. RESULTS: 7-DHC, 25(OH)D3 and vitamin D metabolic ratio (VDMR) were significantly lower in CRC patients than in control group (P<0.001, P<0.010, P<0.050 and P<0.050, respectively). 25(OH)D3 levels were higher in patients with grade I CRC when compared to grade II (P<0.050). All vitamin D metabolites positively correlated with total cholesterol (TC) concentration in CRC patients. 25(OH)D3 was significant predictor of increased CRC risk (P<0.010). After adjustment for TC concentration, 25(OH)D3 lost its predictive abilities. However, 25(OH)D3 remained significant predictor of poorly differentiated type of cancer (P<0.050). CONCLUSIONS: We found significant positive association between vitamin D status and serum total cholesterol. Although low 25(OH)D3 was found to be a significant risk factor for CRC development, the obtained results primarily suggest profound impact of cholesterol level on vitamin D status in CRC. However, our results suggest that low 25(OH)D3 might independently contribute to development of poorly differentiated tumor.

Association among resistin, adenylate cyclase-associated protein 1 and high-density lipoprotein cholesterol in patients with colorectal cancer: a multi-marker approach, as a hallmark of innovative predictive, preventive, and personalized medicine.

BACKGROUND: Elevated concentrations of resistin have been reported in colorectal cancer (CRC), but its interactions with adenylate cyclase-associated protein 1 (CAP-1) are largely unexplored. We investigated resistin plasma concentration, peripheral blood mononuclear cells (PBMCs) resistin messenger ribonucleic acid (mRNA), and CAP-1 mRNA levels in CRC patients, as well as the impact of resistin gene polymorphism rs1862513 on the examined markers. We also explored associations of resistin with high-density lipoprotein cholesterol (HDL-C) and predictive potential of our parameters for CRC. METHODS: Eighty-six patients with CRC and 75 healthy adults were included. Commercial ELISA kit was used for obtaining resistin's concentrations, while polymerase chain reaction (PCR) method was applied for evaluation of resistin and CAP-1 mRNA levels and rs1862513 polymorphism. RESULTS: Plasma resistin and CAP-1 mRNA levels were higher in CRC patients (p < 0.001 and p < 0.05, respectively), while resistin mRNA levels were lower (p < 0.001). Negative association existed among plasma resistin and HDL-C concentrations (ρ = - 0.280; p < 0.05). A model including age, body-mass index, HDL-C, low-density lipoprotein cholesterol (LDL-C), and plasma resistin concentrations as independent predictors of CRC showed very good diagnostic accuracy (AUC = 0.898). We found no associations of rs1862513 with the examined markers. CONCLUSIONS: Our study demonstrated increased plasma resistin and CAP-1 mRNA levels, implying their possible interaction in CRC. The association among plasma resistin and HDL-C might indicate that HDL-C is involved in alterations of resistin's secretion process. As a hallmark of personalized medicine, multi-marker approach in determination of resistin-related parameters might be useful for prediction and prevention of CRC development.

Changes in lecithin: cholesterol acyltransferase, cholesteryl ester transfer protein and paraoxonase-1 activities in patients with colorectal cancer.

BACKGROUND: Previous studies revealed decreased level of high-density lipoprotein cholesterol (HDLC) as important factor for development of colorectal cancer (CRC). Quantity and structure of HDL particles depend on activities of lipid transfer proteins lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), but this topic is largely unexplored in CRC. The main objective of this study was to investigate activities of LCAT and CETP in patients with CRC. Additionally, we analyzed activity of paraoxonase-1 (PON-1), as a main carrier of HDL-antioxidant function. MATERIALS AND METHODS: Ninety-nine CRC patients and 101 healthy individuals were included. LCAT and CETP activities were assessed by measuring rates of formation and transfer of cholesteryl esters. PON-1 paraoxonase and arylesterase activities were measured. RESULTS: Lower levels of HDL-C (p < .001) were observed in cohort of patients, alongside with decreased LCAT (p < .050) and increased CETP activity (p < .050). Both PON-1 activities were diminished in CRC (p < .050 and p < .001 respectively). Univariate logistic regression singled out HDL-C level (OR = 0.218, p < .001), CETP activity (OR = 1.010, p < .01) and mass (OR = 0.994, p < .001) as possible markers of elevated CRC risk. CETP mass maintained its predictive significance when adjusted for traditional risk factors and level of oxidative stress (OR = 0.993, p < .001; OR = 0.982, p < .050, respectively). CONCLUSION: Our results demonstrated increased CETP and decreased LCAT and PON-1 activities in CRC patients. In preliminary analysis CETP mass was identified as potential significant predictor of CRC development, suggesting that alterations in HDL-C levels, alongside with changes in HDL structure might have a role in carcinogenesis.

Significance of LDL and HDL subclasses characterization in the assessment of risk for colorectal cancer development.

INTRODUCTION: Dyslipidaemia contributes to the occurrence of colorectal cancer (CRC). We hypothesized that qualitative changes of lipoproteins are associated with the risk for CRC development. This study analyses low-density lipoprotein (LDL) and high-density lipoprotein (HDL) diameters, as well as distribution of LDL and HDL subclasses in patients with CRC, with an aim to determine whether advanced lipid testing might be useful in predicting the risk for the onset of this malignancy. MATERIALS AND METHODS: This case-control study included 84 patients with newly diagnosed CRC and 92 controls. Gradient gel electrophoresis was applied for separation of lipoprotein subclasses and for LDL and HDL diameters determination. Lipid parameters were measured using routine enzymatic methods. RESULTS: Total cholesterol, HDL and LDL-cholesterol were significantly lower in CRC patients compared to controls (4.47 mmol/L vs. 5.63 mmol/L; 0.99 mmol/L vs. 1.27 mmol/L; 2.90 mmol/L vs. 3.66 mmol/L; P < 0.001, respectively). Patients had significantly smaller LDL (25.14 nm vs. 26.92 nm; P < 0.001) and HDL diameters (8.76 nm vs. 10.17 nm; P < 0.001) and greater proportion of small, dense LDL particles (54.0% vs. 52.9%; P = 0.044) than controls. Decreased LDL and HDL diameters were independent predictors of CRC (OR = 0.5, P = 0.001 and OR = 0.5, P = 0.008, respectively), and alongside with age and HDL-cholesterol concentrations formed the optimal cost-effective model, providing adequate discriminative abilities for CRC (AUC = 0.89) and correct patients classification (81%). CONCLUSIONS: Patients with CRC have decreased LDL and HDL diameters and increased proportion of smaller particles. LDL and HDL diameters determination could be useful in assessing the risk for CRC development.

Relationship between of short-course preoperative radiotherapy and serum albumin level and postoperative complications in rectal cancer surgery.

BACKGROUND/AIM: The identification of risk factors could play a role in improving early postoperative outcome for rectal cancer surgery patients. The air of this s5udy was to determine the relationship between short-course preoperative radiotherapy (RT), serum albumin level and the development of postoperative complications in patients after anterior rectal resection due to rectal cancer without creation of diverting stoma. METHODS: This retrospective study included patients with histopathologically confirmed adenocarcinoma of the rectum with the clinical stage of T2-T4 operated on between 2007 and 2012. All the patients underwent open anterior rectal resection without diverting stoma creation. Preoperative serum albumin was measured in each patient. Tumor location was noted intraoperatively as the distance between the inferior tumor margin and anal verge. Tumor size was measured and noted by the pathologist who assessed specimens. Some of the patients received short-course preoperative RT, and some did not. The patients were divided into two groups (group 1 with short-course preoperative RT, group 2 without short-course preoperative RT). Postoperative complications included clinically apparent anastomotic leakage, wound infection, diffuse peritonitis and pneumonia. They were compared between the groups, in relation to preoperative serum albumin level, patient age, tumor size and location. RESULTS: The study included 107 patients (51 in the group 1 and 56 in the group 2). There were no significant difference in age (p = 0.95), gender (p = 0.12) and tumor distance from anal verge (p = 0.53). The size of rectal carcinoma was significantly higher in the group 1 than in the group 2 (51.37 +/- 12.04 mm vs. 45.57 +/- 9.81 mm, respectively; p = 0.007). The preoperative serum albumin level was significantly lower in the group 1 than in the group 2 (34.80 +/- 2.85 g/L vs. 37.55 +/- 2.74 g/L, respectively; p < 0.001). A significant correlation between the tumor size and the serum albumin level was found (p = 0.042). Overall, postoperative complications were observed in 13 (25.5%) patients in the group 1 and in 10 (17.8%) patients in the group 2 without significant difference between the groups (p = 0.18). A significantly lower level of serum albumin was found in patients with postoperative complications and in those who died. A significant difference in anastomotic leakage occurrence between groups was found (p = 0.039). Male gender and the lower level of serum albumin were significant predictors for anastomotic leakage occurrence (p = 0.05 and p = 0.002, respectively), but preoperative RT had no significant impact on it. CONCLUSIONS: A lower serum albumin level, but not short-course of preoperative RT, was significantly associated with postoperative complications development after rectal resection with' out diverting stoma.