The main regulator of anti-tumor immune response is the activity of monocytes, suggesting that the produced cytokines may have a prognostic role. This study investigates gene expression of interleukin (IL)-12-related cytokine and IL-10 in stimulated monocytes from colorectal cancer (CRC) patients. Relative quantification of IL-12A, IL-12B, IL-23A and IL-10 mRNA transcripts was performed on the third hours after stimulation by real-time qPCR. We also explored an inhibitor of JNK signaling pathway activation for the observed cytokine gene expression. A strong downregulation of IL-12B mRNA expression in CRC monocytes compared to healthy donors was observed. The rate of transcription of IL-12B in stimulated monocytes was associated with the stage of CRC. The expression of IL-12A gene in stimulated monocytes from patients with advanced was lower than early cancer. Moreover, we observed stage dependent JNK inhibition mediated reduction in IL-12A expression. The hyporesponsiveness was strongly expressed in monocytes from advanced then early stages of CRC. Expression of IL-10 mRNA was almost equally in CRC monocytes from early stages and healthy donors. We demonstrated that altered gene expression profiles of IL-12A, IL-12B, IL-23A at mRNA level in CRC monocytes was associated with tumor development and can be attributed to anticancer immune response.
T helper 17 (Th17) and T regulatory (Treg) cytokines appear to be contributing greatly to colorectal cancer (CRC) development and progression. The aim of the current study was to investigate the expression of Foxp3; IL10; TGFB1; IL17A; IL6 and NOS2 genes in tumor tissue, regional positive lymph nodes and distant metastasis obtained from 26 patients with advanced CRC. Quantitative real-time polymerase chain reaction (qPCR) was performed for mRNA detection by TaqMan gene expression assay. In distant metastasis, IL6 was strongly expressed, over 7.5 fold, followed by Treg-related genes Foxp3; IL10 and TGFB1 in contrast to IL17A and NOS2. The similar pattern of expression was observed in positive regional lymph node in addition to significant down-regulation of NOS2 (RQ = 0.287; p = 0.011) and a trend for the elevation of IL17A. In tumor tissue, Fopx3 was significantly upregulated and Foxp3 mRNA positively correlated with TGFB1 in all investigated tissue types. In tumor tissue, expression of IL17A was correlated with NOS2 (r = 0.68; p = 0.005), while in distant metastasis IL10 was in strong relation with TGFB1 and IL6. In addition, a reverse correlation between IL6 and NOS2 (r = -0.66; p = 0.009), was observed in distant metastasis. The simultaneous expression of given Treg and Th17-related genes found both in the primary tumor and in the regional lymph nodes appears to provide suitable microenvironment sufficient for promoting metastatic growth. The upregulation of Foxp3; IL10, TGFB1 and IL6 might be a transcriptional profile hallmark for colorectal metastases.
Colorectal cancer (CRC) patients were previously shown to express a signature of cytokines that contribute to cancer pathogenesis and are detectable in serum. The aim of this study was to evaluate the potential clinical use of circulating cytokine measurements in CRC patients preoperatively as markers for disease outcome. The levels of cytokines IL-12p40 and IL-23 were assessed by ELISA in the sera of 91 patients with previously untreated CRC and then 5-year survival was determined using Kaplan-Meier analyses. The levels of circulating interleukin IL-12p40 significantly decreased with the progression of CRC, whereas the levels of IL-23 remained with no significant differences between disease stages. None of the cytokine levels were influenced by age, gender and colon vs rectum localization. We found that preoperative serum concentration of IL-12p40 cytokine is a good prognostic marker for survival; as for IL-23 levels, we found no outcome prognostic value. In addition, 5-year survival confirmed that tumor grade, bowel wall invasion, lymph node and metastatic status have an impact on overall survival. In conclusion, we believe that our findings show clinical significance of the preoperative serum concentration for IL-12p40 and provide an additional prognostic biomarker for CRC survival.
Aim of the studyThe ability of immune cells in peripheral blood to produce certain cytokines affects tumour-elicited inflammation. The aim of this study was to investigate the gene expression of interleukin 12A (IL-12A), IL-12B, IL-23A, IL-10, IL-6, transforming growth factor β (TGF-β), HDAC3, and iNOS in peripheral blood mononuclear cells (PBMC) from colorectal cancer (CRC) patients.Material and methodsThe venous blood for PBMC isolation was collected preoperatively and 10 days after surgery, from CRC patients. After isolation of total RNA and synthesis of cDNA, quantitative real-time PCR assays were performed.ResultsOur results demonstrated that among investigated cytokine genes IL-10 and TGF-β were significantly upregulated in patients with CRC compared to the control group, while the expression of IL-23 mRNA was significantly decreased in CRC patients. We observed significantly increased mRNA levels in CRC patients’ PBMC before surgery for IL-10 and TGF-β compared to both postoperative and control groups. We also found a significant upregulation of iNOS in early compared to advanced CRC.ConclusionsBased on the results we can assume that PBMC gene expression programming in CRC patients drives local differentiation of Th cells towards Treg instead of the Th1 anti-tumour subpopulation.
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