| 31. |
- Dimberg, Jan
(författare)
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Studies on expression and regulation of phospholipase A2 and cyclooxygenase 2 in gastrointestinal tissues with special reference to colorectal cancer
- 1999
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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.
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| 32. |
- Elander, Nils, et al.
(författare)
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Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer
- 2009
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Ingår i: Molecular Carcinogenesis. - : Wiley. - 0899-1987 .- 1098-2744. ; 48:5, s. 401-407
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Tidskriftsartikel (refereegranskat)abstract
- Bioactive metabolites downstream of cyclooxygenase-2 (COX-2) generated prostaglandin H-2 (PGH(2)), in particular prostaglandin E-2 (PGE(2)), are thought to play critical roles during the development of colorectal tumors. Previous reports reveal that defects of the tumor suppressor adenomatosis polyposis coli (APC) contribute to COX-2 upregulation in colon tumor cells. We investigated whether a similar relation was present between APC functional status and the expression of microsomal prostaglandin E synthase-1 (mPGES-1), which acts downstream of COX-2 and catalyses the terminal conversion of PGH(2) into PGE(2). Surprisingly, mPGES-1 mRNA and protein levels were upregulated upon induction of a wild type-APC carrying vector in HT29 colon cancer cells, and downregulated following siRNA silencing of APC in HCT-116 cells. mPGES-1 was overall enhanced in human colorectal tumor specimens versus corresponding non-tumor mucosa and, in accordance with data on HT29 and HCT116 cells, higher levels of mPGES-1 were observed among tumors carrying wild type versus mutant APC. RNAi silencing of beta-catenin and luciferase assays regarding the mPGES-1 promoter region did not reveal a role for APC or beta-catenin/Tcf in controlling mPGES-1 gene transcription. However, RNA degradation assays in HT29 cells revealed a suppressed degradation of mPGES-1 in the presence of wild type APC, implying that mPGES-1 mRNA is stabilized in the APC wild type state. Collectively, we demonstrate a novel association between APC functional status and mPGFS-1 expression in colorectal tumor cells, being most likely related to reduced mPGES-1 mRNA degradation rate in the APC wild type state.
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| 33. |
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| 36. |
- Gabrielson, Marike, et al.
(författare)
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Altered PPARγ coactivator-1 alpha expression in abdominal aortic aneurysm : Possible effects on mitochondrial biogenesis
- 2016
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Ingår i: Journal of Vascular Research. - : S. Karger. - 1018-1172 .- 1423-0135. ; 53:1-2, s. 17-26
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Abdominal aortic aneurysm (AAA) is a complex and deadly vascular disorder. The pathogenesis of AAA includes destruction and phenotypic alterations of the vascular smooth muscle cells (VSMCs) and aortic tissues. PPARγ coactivator-1 alpha (PGC1α) regulates VSMC migration and matrix formation and is a major inducer of mitochondrial biogenesis and function, including oxidative metabolism. Methods: Protein and gene expression of PGC1α and markers for mitochondria biogenesis and cell type-specificity were analysed in AAA aortas from humans and mice and compared against control aortas. Results: Gene expression of PPARGC1A was decreased in human AAA and angiotensin (Ang) II-induced AAA in mice when compared to control vessels. However, high expression of PGC1α was detected in regions of neovascularisation in the adventitia layer. In contrast, the intima/media layer of AAA vessel exhibited defective mitochondrial biogenesis as indicated by low expression of PPARGC1A, VDAC, ATP synthase and citrate synthase. Conclusion: Our results suggest that mitochondrial biogenesis is impaired in AAA in synthetic SMCs in the media, with the exception of newly formed supporting vessels in the adventitia where the mitochondrial markers seem to be intact. To our knowledge, this is the first study investigating PGC1α and mitochondria biogenesis in AAA.
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| 37. |
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| 40. |
- Mumtaz, Melad, et al.
(författare)
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Decreased expression of the chemokine CCL21 in human colorectal adenocarcinomas
- 2009
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Ingår i: Oncology Reports. - : Spandidos Publications. - 1021-335X .- 1791-2431. ; 21:1, s. 153-158
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have revealed participation of chemokines in cancer by regulating leukocyte movement to modify local immunoresponse. The chemokine CCL21 has been identified to play a pivotal role in homing and localization of immune cells to lymphoid tissue and into organ of non-lymphoid origin. In the cancer biology CCL21 seems to have multifaceted roles. CCL21 attracts CCR7 bearing cells especially T and dendritic cells but also various cancer cells. Besides the antitumour role as leukocyte recruiting, CCL21 has been shown to facilitate dendritic cell functions and to exert an angiostatic effect. To gain insight into the possible influence of CCL21 oil colorectal cancer (CRC) we determined whether the CCL21 is altered in CRC tissue. Collectively, by using ELISA we noted a significant lower CCL21 level in cancer tissue compared with paired normal tissue. Patients with a tumour localized in the rectum revealed significantly lower level of CCL21 than patients with a tumour localized in the colon both compared with paired normal tissue. We used immunohistochemistry and found heterogeneous immunoreactivity predominantly within areas of stromal cells mainly in macrophages. We also used a TaqMan system to investigate two single-nucleotide polymorphisms rs 11574915 and rs 2812377 with Supposed effect on CRC. No significant difference was observed between CRC and control subjects regarding genotype and allelic distributions or associations to clinical characteristics or CCL21 tissue levels. Our study implied that lower level of CCL21 in CRC tissue supports the idea that cancer is related to immunodeficiency probably depending on regulatory factors produced by tumour cells and that the different levels of CCL21 in rectum and colon may reflect divergent mechanisms in colorectal carcinogenesis. Further studies are needed to clarify whether the CCL21 level has an impact on CRC progression and survival rate.
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