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Inflammation-associated genes and genetic variations in colorectal cancer
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer is a major cause of morbidity and mortality around the world, each year affecting about one million individuals worldwide. The disease is characterized by an accumulation of genetic alterations, and a sequence of events leading to the development of an invasive and metastasising tumour. Chronic or dysregulated inflammation may contribute to tumour initiation and progression via the release and activity of various mediators – e.g. cytokines, prostaglandins, inducible nitric oxide synthase (NOS2), matrix metalloproteinases (MMPs), and vascular endothelial growth factors (VEGF). In the present thesis, genes and genetic alterations controlling these events were analysed and discussed within the context of colorectal cancer.

Prostaglandins, being generated from arachidonic acid in reactions dependent on cyclooxygenases (COX-1, COX-2), have been implicated in carcinogenesis of many organs. Since the quite recent characterization of the terminal and specific prostaglandin synthases, which act downstream of COX enzymes, the search for molecular targets which selectively suppress individual prostanoids has been intensified. In papers I-II, the role and regulation of inducible prostaglandin E2 (PGE2) synthase - mPGES-1 - were explored within the context of intestinal cancer. mPGES-1 was genetically deleted in the ApcMin/+ mouse - yielding marked suppression of PGE2 generation in intestinal and tumour tissue. However, a shift towards enhanced generation of non-PGE2 prostanoids was observed in mPGES-1 knock out mice, and these mice developed more and larger instestinal tumours. These results therefore indicate that targeting mPGES-1 may paradoxically promote tumourigenesis, most likely by secondary effects on other potentially pro-tumoural mediators. We also explored the relation of the commonly mutated APC gene and mPGES-1 in colon tumour cells, and found that high expression of mPGES-1 was associated with the presence of wild type APC. Rather than by regulating putative β-catenin/Tcf binding sites of the mPGES-1 promoter, APC seems to influence the stabilisation of mPGES-1 mRNA.

In papers III-V, the possible contribution of variations in regulatory regions of genes encoding NOS2, MMPs, and VEGF, was assessed in populations of colorectal cancer patients and healthy control individuals. A single nucleotide insertion (1G/2G) at -1607 upstream the transcription start site of the MMP-1 gene was identified to be a susceptibility factor for colorectal cancer development, although no relation with disease characteristics was observed. Except for a rather uncommon combination of two individual polymorphisms of the VEGF gene, investigated genetic variations of VEGF, other MMPs, and NOS2, were not associated with colorectal cancer susceptibility or clinicopathological characteristics. We therefore suggest that other molecular events play more significant roles for the dysregulation of these genes in colorectal tumours.

In summary, accumulating evidence, including the results here presented, suggest significant albeit complex roles of inflammation-induced genes and mediators in colorectal tumourigenesis. The present results may aid in identifying or excluding potential biomarkers and drug targets within cancer-related inflammation.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 54 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1146
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-54811ISBN: 978-91-7393-560-9 (print)OAI: oai:DiVA.org:liu-54811DiVA: diva2:310528
Public defence
2009-09-11, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2010-05-04Bibliographically approved
List of papers
1. Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice
Open this publication in new window or tab >>Genetic deletion of mPGES-1 accelerates intestinal tumorigenesis in APCMin/+ mice
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2008 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 372, no 1, 249-253 p.Article in journal (Refereed) Published
Abstract [en]

The induced synthesis of bioactive prostanoids downstream of cyclooxygenase-2 (COX-2) and prostaglandin H2 (PGH2) exerts a critical event in colorectal carcinogenesis. Here we demonstrate that APCMin/+ mice with genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), which catalyses the terminal conversion of PGH2 into PGE2, surprisingly develop more and generally larger intestinal tumors than do mPGES-1 wild type littermates (mean number of tumors/intestine 80 vs. 38, p < 0.0005, mean tumor diameter 1.64 vs. 1.12 mm, p < 0.0005). No deviation regarding the expression of other PGE2 related enzymes (COX-1, COX-2, mPGES-2, cPGES, and 15-PGDH) or receptors (EP1-4) was obvious among the mPGES-1 deficient mice. PGE2 levels were suppressed in tumors of mPGES-1 deficient animals, but the concentrations of other PGH2 derived prostanoids were generally enhanced, being most prominent for TxA2 and PGD2. Thus, we hypothesise that a redirected synthesis towards other lipid mediators might (over)compensate for loss of mPGES-1/PGE2 during intestinal tumorigenesis. Nevertheless, our results question the suitability for mPGES-1 targeting therapy in the treatment or prevention of colorectal cancer. © 2008 Elsevier Inc. All rights reserved.

Keyword
6-Ketoprostaglandin F1 alpha/analysis Animals Cell Transformation, Neoplastic/*genetics/pathology Colorectal Neoplasms/*genetics/pathology Dinoprostone/analysis/*metabolism Female *Gene Deletion Intramolecular Oxidoreductases/*genetics Male Mice Mice, Mut
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-43256 (URN)10.1016/j.bbrc.2008.05.026 (DOI)73147 (Local ID)73147 (Archive number)73147 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2011-12-14Bibliographically approved
2. Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer
Open this publication in new window or tab >>Association Between Adenomatosis Polyposis Coli Functional Status and Microsomal Prostaglandin E Synthase-1 Expression in Colorectal Cancer
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2009 (English)In: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 48, no 5, 401-407 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
cyclooxygenase 2, Prostaglandin E-2, beta-catenin, adenomatosis polyposis coli (APC), microsomal prostaglandin E synthase-1 (mPGES-1), colorectal cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18549 (URN)10.1002/mc.20500 (DOI)
Available from: 2009-06-01 Created: 2009-06-01 Last updated: 2011-12-14Bibliographically approved
3. Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer
Open this publication in new window or tab >>Nitric oxide synthase 2 (NOS2) promoter polymorphisms in colorectal cancer
2005 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 225, no 1, 99-103 p.Article in journal (Refereed) Published
Abstract [en]

Previously, increased expression of nitric oxide synthase 2 (NOS2) in colorectal cancer (CRC) has been identified. The NOS2 gene is transcriptionally regulated, which suggests that polymorphisms in the NOS2 promoter may have a role for CRC development and progression. The genotyping was performed with PCR/RFLP, single strand conformation analysis or MegaBACE genotyping of normal blood DNA from CRC patients and normal healthy controls. However, no significant association between NOS2 polymorphisms and CRC onset or clinical outcome was evident. In conclusion, these results, therefore, suggest that NOS2 promoter polymorphisms have a limited effect on the onset or progression of CRC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-30426 (URN)10.1016/j.canlet.2005.02.006 (DOI)15988 (Local ID)15988 (Archive number)15988 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-25Bibliographically approved
4. Martix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer
Open this publication in new window or tab >>Martix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer
2006 (English)In: Anticancer Research, ISSN 0250-7005, Vol. 26, no 1 B, 791-795 p.Article in journal (Refereed) Published
Abstract [en]

Background: Matrix metalloproteinases (MMPs) are a group of matrix-degrading proteins implicated in several pathological processes, e.g., invasion and metastasis in malignant diseases such as colorectal cancer (CRC). Materials and Methods: One hundred and twenty-seven CRC patients and 208 controls were genotyped for MMP-1, -2, -3 and -9 promoter polymorphisms. The genotyping was performed with PCR/primer-extension/DHPLC or PCR/RFLP. Results: The MMP-1 2G allele was significantly associated with CRC (p=0.037). No significant association between CRC and MMP-2, -3 or -9 polymorphisms was evident. The analysis of polymorphisms in the clinicopathological subgroups displayed no significant associations. Conclusion: The MMP-1 promoter polymorphism seems to affect the susceptibility to CRC, while MMP-2, -3 and -9 polymorphisms appear less likely to have any impact on CRC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-37785 (URN)38605 (Local ID)38605 (Archive number)38605 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2010-04-14
5. Analysis of VEGF polymorphisms, tumor expression of VEGF mRNA and colorectal cancer susceptibility in a Swedish population
Open this publication in new window or tab >>Analysis of VEGF polymorphisms, tumor expression of VEGF mRNA and colorectal cancer susceptibility in a Swedish population
2009 (English)In: MOLECULAR MEDICINE REPORTS, ISSN 1791-2997, Vol. 2, no 3, 435-439 p.Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor (VEGF) plays a significant role in tumor angiogenesis and is found to be overexpressed and involved in the development and progression of colorectal cancer (CRC). The VEGF gene contains several polymorphic sites known to influence VEGF expression. We examined the possible association between five polymorphisms, located in the promoter/5-untranslated region [-2578 (C/A), -2549 (del/ins 18 bp) -1154 (G/A), -634 (G/C)] or 3-untranslated region [+936 (C/T)] of the VEGF gene, and CRC Susceptibility and clinicopathological characteristics in 302 Swedish CRC patients and 336 healthy randomly selected controls. Both genotypes and combined haplotypes were analyzed. No significant differences were observed when VEGF genotype/haplotype frequencies in the CRC cases and controls were compared, nor were any associations found between the genotypes/haplotypes and clinicopathological characteristics. However, when the -2578 C and +936 T alleles were combined, a small but significant association with CRC susceptibility was detected (OR=1.6, 95% CI 1.3-1.9, p=0.01). In addition, VEGF mRNA expression was determined in a Subset of patients, revealing a 2-fold VEGF upregulation in CRC tissue compared to normal colonic mucosa, but no association between the genotypes or haplotypes and VEGF mRNA levels. Linkage analysis was performed, revealing that the polymorphisms in the promoter and 5-untranslated region were in tight linkage disequilibrium (LD) (vertical bar Dvertical bar=0.91-1.00), while the +936 C/T polymorphism was only weakly associated with the others (vertical bar Dvertical bar=0.05-0.19). In conclusion, VEGF is generally upregulated in colorectal tumors. However, the single nucleotide polymorphisms examined do not appear to influence the mRNA expression of VEGF in colorectal tumors, and most likely play a limited role in CRC development and progression.

Keyword
vascular endothelial growth factor, colorectal cancer, mRNA, single nucleotide polymorphism, haplotype analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18021 (URN)10.3892/mmr_00000118 (DOI)
Available from: 2009-05-04 Created: 2009-05-04 Last updated: 2014-09-11

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