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Nitric oxide synthase 2 mRNA expression in relation to p53 and adenomatous polyposis coli mutations in primary colorectal adenocarcinomas
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
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2002 (English)In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 131, no 4, 384-392 p.Article in journal (Refereed) Published
Abstract [en]

Background. The inducible nitric (NO) synthase 2 (NOS2) is upregulated in breast, brain, colon, and gynecological tumors, which indicate that NO may have a role in tumorigenesis. However, little is known about the role and regulation of NOS2 in colorectal carcinomas. Recent in vitro experiments have implicated that NOS2 is downregulated by p53 accumulation. Virtual analysis of the NOS2 promoter showed putative TCF-4/Lef-1 response elements, which indicate a potential regulation of NOS2 expression by activation of the adenomatous polyposis coli (APC)/β-catenin pathway.

Methods. NOS2 mRNA expression was investigated in 59 colorectal carcinomas by reverse transcriptase/real-time polymerase chain reaction and related to mutations in the p53, APC, and β-catenin genes. Presence of NOS2 protein was studied by Western blot, and the localization was studied by immunohistochemistry. Loss of heterozygosity was studied in the region of the NOS2 gene.

Results. The NOS2 mRNA and protein expression were significantly higher in tumors than in control tissue. Immunohistochemistry revealed extensive NOS2 staining in the epithelial cells and, to a minor degree, in leukocytes. Increased NOS2 mRNA expression was found in Dukes' stages A and B compared with the C and D stages. No relationship was found between elevated NOS2 expression and loss of heterozygosity in the later stages according to Dukes' classification or mutations in the p53, APC, or β-catenin genes.

Conclusions. Inactivating mutations in the p53 and APC pathways are not the main explanation for the increased NOS2 expression found in colorectal tumors.

Place, publisher, year, edition, pages
2002. Vol. 131, no 4, 384-392 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25021DOI: 10.1067/msy.2002.121888Local ID: 9442OAI: oai:DiVA.org:liu-25021DiVA: diva2:245346
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-09-25Bibliographically approved
In thesis
1. Molecular genetic aspects of colorectal cancer development
Open this publication in new window or tab >>Molecular genetic aspects of colorectal cancer development
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer (CRC) is one of the most common cancer diseases in the world after lung and female breast cancer and approximately 945 000 new cases are diagnosed every year. CRC is caused by genetic alterations in the DNA, which results in cell cycle acceleration, escape from apoptosis, senescence, angiogenesis, invasion and metastasis. In this thesis, we have investigated molecular genetic alterations for the development of CRC and focused on the MAPK pathway, HIF-1 α and NOS2 genes.

Alterations in the MAPK pathway have been found in several different cancer forms, including CRe. In the present study, we found somatic mutations in the MAPK pathway in 50% of the CRCs; 40% of the tumors carried mutations in the KRAS gene and 10% carried BRAF mutations. No genetic alterations were found in the ARAF or RAF-1 genes. B&4F gene mutations were present only in exon 15 and were associated with micro satellite instability. Three mutation types were identified; V599E, D593G and K600N, whereof the latter has not previously been described.

The hypoxia inducible factor (HIF)-la protein is involved in the oxygen sensing mechanism and several tumor types show HIF-la overexpression due to hypoxia. At normoxia, HIF-la is degraded by interaction with the von Hippel-Lindau (VHL) tumor suppressor protein followed by an ubiquitin-proteasome dependent degradation mechanism, which prevents HIF-l a from nuclear translocation and transcription of downstream target genes. Fifteen percent of CRC patients and normal healthy population was found to carry the P582S polymorphism in the HIF-1 α gene, which previously has been associated to higher transactivating capacity. In the present study, the polymorphism was associated to ulcerative tumor development. In addition, loss of heterozygosity of the wild type P582 allele in heterozygotes may contribute to the development of ulcerative CRCs. However, the overall mechanism for ulcerative tumor development is still unclear.

Nitric oxide (NO) is involved in several physiological processes, such as apoptosis, neurotransmission, angiogenesis and immune defence and is produced by three nitric oxide synthases; NOSl-3. In the present study, NOS2 upregulation was identified in CRCs compared to normal intestinal mucosa. Moreover, the contribution of NOS2 in CRC development was investigated in APCMin/+ and APCMin/+ NOS2-/- mice. The APCMin/+ NOS-/- mice developed a higher polyp frequency compared to APCMin/+ mice, indicating a protective role for the presence of NOS2 in intestinal cancer development. The elevated polyp formation in the APCMin/+ NOS-/- mice was independent of the expression of Notch-l and p21. We also investigated whether polymorphisms in the NOS2 promoter affected the onset of CRC, but no differences in allele or genotype frequencies were observed in normal healthy population compared to CRC patients.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2005. 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 878
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31156 (URN)16894 (Local ID)91-7373-856-5 (ISBN)16894 (Archive number)16894 (OAI)
Public defence
2005-01-21, Berzeliussalen, Halsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-25Bibliographically approved

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Fransén, KarinSöderkvist, Peter

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