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Martix metalloproteinase (MMP) -1, -2, -3 and -9 promoter polymorphisms in colorectal cancer
Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för medicinsk cellbiologi.
2006 (engelsk)Inngår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, nr 1 B, s. 791-795Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2006. Vol. 26, nr 1 B, s. 791-795
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-37785Lokal ID: 38605OAI: oai:DiVA.org:liu-37785DiVA, id: diva2:258634
Tilgjengelig fra: 2009-10-10 Laget: 2009-10-10 Sist oppdatert: 2017-12-13
Inngår i avhandling
1. Inflammation-associated genes and genetic variations in colorectal cancer
Åpne denne publikasjonen i ny fane eller vindu >>Inflammation-associated genes and genetic variations in colorectal cancer
2009 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2009. s. 54
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1146
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-54811 (URN)978-91-7393-560-9 (ISBN)
Disputas
2009-09-11, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2010-04-14 Laget: 2010-04-14 Sist oppdatert: 2010-05-04bibliografisk kontrollert

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