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dc.contributor.authorRask, Katarina 1966-en
dc.description.abstractAlterations in cell-cell adhesion, intracellular signaling and transcriptional regulation are common events during transformation of cells to the malignant phenotype. Different cellular defense mechanisms, e.g. inflammatory responses, mediated by prostaglandins, have also been associated with tumor development. In the present thesis, expression and changes of key components involved in the regulation of these events were examined in two common types of human tumors: colorectal cancer (CRC) and epithelial ovarian cancer (EOC). The Wnt signaling pathway, connected to both cell- cell adhesion and transcriptional regulation was explored in EOC. The expression of CCAAT Enhancer Binding Proteins (C/EBPs), a family of transcription factors involved in proliferation, differentiation and apoptosis was examined in CRC. Enzymes responsible for the synthesis of prostaglandin E2 (PGE2), as well as receptors (EP-receptors) for this ligand were investigated in both EOC and CRC. Tissues were obtained from normal ovaries, benign-/borderline tumors, EOC (FIGO classification), normal colon, colon polyps and CRC (staging by Duke´s system). Immunodetection techniques were used for the analysis of expression levels, cell-specific localization and protein-protein interactions. Wingless/Wnt signaling pathway in EOC: Beta-catenin is involved both in cell-cell adhesion, and in transcriptional regulation via the Wingless/Wnt (Wnt) signaling pathway. We demonstrated an increase of b-catenin and GSK-3b in EOC. b-catenin was also co-immunoprecipitated with the transcription factor Lymphocyte enhancer factor-1 (Lef-1) and a-catenin. This suggests a dual role for b-catenin in transcriptional regulation and cell-cell adhesion in EOC. CCAAT Enhancer Binding Proteins in CRC: C/EBPb, a member of a family of transcription factors, plays a central role in cell cycle regulation (proliferation/differentiation) in normal and malignant cells. The contents of C/EBPb were up-regulated in CRC in a Duke´s stage specific manner. A similar pattern with increasing levels in malignant cells was earlier demonstrated in EOC by us. These observations indicate a common function for C/EBPb in tumor transformation and progression, which can involve target genes for enzymes regulating the synthesis of prostanoids, e.g. cyclooxygenases (COXs). COXs, prostaglandin E synthase and EP-receptors in EOC and CRC: We have investigated the expression and cellular localization of cyclooxygenase-2 (COX-2), and other key enzymes in the synthesis of PGE2, and the membrane-bound receptors to which PGE2 binds (EP1-4), in CRC and EOC. Our results support a role for the COX-2- PGE2- EP2- pathway in tumor initiation and progression in CRC. These observations are in agreement with other studies and favor the use of COX-2 specific inhibitors for the prevention and treatment of CRC. The increase we demonstrate of COX-2, microsomal (m)PGES and EP2 in EOC, together with a COX-2 dependent PGE2-production in OVCAR-3 cells, supports the hypothesis that PGE2 is one mediator of prostanoid actions in ovarian tumorigenesis. Conclusions: COX enzymes are key mediators in the synthesis of prostanoids, involved in the inflammatory process, and have been implicated in different types of tumors. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin, well-known inhibitor of COXs, has been shown to cause a reduction in risk of CRC. We have demonstrated low expression of proteins involved in the formation of PGE2, and also of C/EBPb and the proliferation marker PCNA, in benign /borderline ovarian tumors, compared to colon polyps. Therefore, the colon polyps seem to have an increased potential for progression to the malignant phenotype as compared to ovarian benign adenomas/borderline tumors. It is possible that the relatively late expression of the COX-2/PGE2 pathway in the progression of EOC, is one explanation for the reported limited, and sometimes conflicting, effects of NSAIDs for the prevention of EOC.en
dc.subjectCCAAT Enhancer Binding Proteins (C/EBPs)en
dc.subjectWingless/Wnt (Wnt) signaling pathwayen
dc.subjectCyclooxygenases (COXs)en
dc.subjectcolorectal cancer (CRC)en
dc.subjectepithelial ovarian cancer (EOC)en
dc.titleTumor progression in the ovary and colon. The interaction of Wnt-signaling, transcription and formation of prostaglandinsen
dc.type.svepDoctoral thesisen
dc.gup.originGöteborgs universitet/University of Gothenburgeng
dc.gup.departmentDepartment of Physiologyeng
dc.gup.departmentAvdelningen för fysiologiswe
dc.gup.defenceplaceföreläsningssal Gösta Sandels, K2403, kl.09.00en

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