| 1. |
- Dimberg, Jan
(författare)
-
Studies on expression and regulation of phospholipase A2 and cyclooxygenase 2 in gastrointestinal tissues with special reference to colorectal cancer
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The phospholipases A2 (PLA2s) are phospholipid hydrolyzing enzymes that in mammalian cells exist in several different isoform including cytosolic PLA2 (cPLA2), group I PLA2 (PLA2-I) and group II PLA2 (PLA2-ll). PLA2 is involved in production of inflammatory mediators, membrane remodelling, digestive functions and stimulation of prolifemtion. In addition. PLA2 supplies cyclooxygenase COX-1 and COX-2 with arachidonic acid for production of eicosanoids.Increased COX-2 expression and high concentrations of prostaglandins have been found in human colorectal adenocarcinomas and in rat colonic twnours. Studies implicate that there is a link between the tumourigenic effect of the tumour suppressor gene adenomatous polyposis coli (APC) and COX-2 up-regulation in mouse intestinal neoplasms. Mutations of the human APC gene are frequent in both sporadic and familial colorectal cancer and result in activation of p-catenin!T cell factor-4 (Tcf-4) mediated transcription of target genes which may contribute to colorectal tumourigenesis.The ontogenic development of rat gastrointestinal PLA2-I and PLA2-II and the influence of the exogenous glucocorticoid cortisone acetate were studied. The ontogeny of rat glandular stomach PLA2-I and PLA2-II gene expression is similar and seems to follow the general postnatal development of the gastrointestinal tract PLA2-II gene expression is different in the glandular stomach compared to ileum and forestomach during the neonatal period. Administration of the cortisone acetate, during the neonatal period, induced PLA2-I and PLA2-II gene expression in glandular stomach and ileum, respectively, au effect that may be related to maturation of the gastrointestinal tract.Gene expression of PLA2-II, cPLA2 and COX-2, protein levels of COX-2 and mutational analysis of APC were investigated in human colorectal tumours. COX-2 was dramatically up-regulated in tumours located in rectum and associated with the presence of APC mutations. Tcf-4 consensus sequences found in the COX-2 promoter were activated but APC/P-catenin/fcf-4 pathway may partly be involved in transcriptional regulation of the COX-2 gene. Neither induction of PLA2-II nor correlation in gene expression between cPLA2 and COX-2 were observed. 'These observations imply that other enzymes than PLA2 contribute to generate arachidonic acid for COX-2 mediated eicosanoid metabolism aud that PLA2-II seems to play a minor or no role in hllltlan colorectal cancer.
|
|
| 2. |
- Shamoun, Levar, 1979-
(författare)
-
Investigation of immune cell-derived factors as potential biomarkers in patients with colorectal cancer
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
