Investigation of immune cell-derived factors as potential biomarkers in patients with colorectal cancer

Sammanfattning: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related death. It is a heterogeneous disease involving multiple molecular pathways that result in differing phenotypes. Individual variability in CRC susceptibility is influenced by genetic variation, such as single nucleotide polymorphisms (SNPs). Changes in genetics and epigenetics can disrupt intact signalling pathways involved in metabolism, proliferation, differentiation, and apoptosis. Inflammatory factors such as  cytokines and chemokines, as well as their receptors, play important roles in immune regulation.In Papers I, II and III, selected SNPs in the genes of interleukin (IL)-4, IL-13, IL-2 or chemokine C-C motif ligand (CCL) 4 in patients with CRC were investigated to determine their prognostic significance by identifying associations with various clinicopathological parameters and long-term survival. The investigated IL-13 and IL-4 SNPs were found to be risk factors for CRC and could be useful potential prognostic markers in CRC patient follow-up and clinical management. The investigated IL-2 SNPs were significantly associated with an increased risk of CRC and worse cancer-specific survival in patients with stage II or stage III CRC.In Paper III, levels of CCL4 protein were measured in CRC patients to investigate their prognostic significance for CRC. The data showed that CRC tissue had a higher protein expression than normal paired tissue, and plasma CCL4 levels were higher in patients than in controls, being positively correlated with CRC tissue levels. Further, higher levels of tissue CCL4 protein were linked to a lower disease stage and a better prognosis.Paper IV was an investigation of the expression of zinc finger MYND-type containing 15 (zmynd15) and its roles in CRC. In CRC tissue, protein expression was found primarily in cluster of differentiation (CD) 68 positive cells. Zmynd15 messenger ribonucleic acid expression was lower in CRC tissue than in non-cancerous tissue. When zmynd15 was silenced in CRC cell lines, it caused alteration in genes known to be important in CRC, indicating that zmynd15-regulated genes are involved in CRC. Furthermore, tumour development in the colon was higher in zmynd15 knockout mice than in wild-type mice.In conclusion, the work presented in this thesis contributes to an understanding of the association of inflammatory markers in CRC with risk and survival, and their potential use as tools for monitoring CRC patients. In addition, it showed that zmynd15, a transcriptional suppressor, plays an important role in the development of CRC.