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Loss of Glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma
University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences.
Örebro University Hospital.
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2010 (English)In: Cancer Cell International, ISSN 1475-2867, Vol. 10, 46- p.Article in journal (Refereed) Published
Abstract [en]

Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.

Place, publisher, year, edition, pages
BioMed Central, 2010. Vol. 10, 46- p.
Keyword [en]
Gpx3, endometrial cancer, methylation, real time PCR, FIGO grades
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
URN: urn:nbn:se:his:diva-4708DOI: 10.1186/1475-2867-10-46ISI: 000285883400001Scopus ID: 2-s2.0-78549258157OAI: oai:DiVA.org:his-4708DiVA: diva2:394209
Available from: 2011-02-02 Created: 2011-02-02 Last updated: 2013-04-09Bibliographically approved
In thesis
1. Genomic and genetic alterations in endometrial adenocarcinoma
Open this publication in new window or tab >>Genomic and genetic alterations in endometrial adenocarcinoma
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The most frequently diagnosed cancer of the female genital tract is cancer of the endometrium (endometrial cancer), ranking fourth among the invasive tumors that affect women in Europe and North America. As most other cancer types, endometrial cancer is a complex genetic disease influenced by both genetic and environmental factors.

The human population is genetically heterogeneous and studies of complex diseases in human are proven to be difficult. By using a model system such as the BDII rat, some of the obstacles related to the study of complex diseases can be avoided. The BDII rat strain is prone to spontaneously develop endometrial adenocarcinoma (EAC) and more than 90% of the virgin females develop EAC during their lifetime. Development of EAC tumors in BDII rats is comparable in pathogenesis and histopathological properties to that of human.

The aims of this thesis were i/ to characterize EAC in the BDII rat experimental model system by analyzing structural and numerical chromosome aberrations, ii/ to evaluate the importance of the genetic set-up in EAC development, and iii/ to determine the impact of genomic and genetic alterations on the functionality of candidate genes in rat EAC and in human endometrial tumors of different FIGO grades.

Non-random numerical and structural aberrations that could contribute to tumor formation were identified, and evidence that the genetic background had a significant influence on the genome make-up of tumor cells was provided. Certain genes (Gpx3/GPX3, Met/MET, Phf5a/PHF5A, and Gja1/GJA1) were selected for further analysis and aberrant expression of some of them were found in both rat and human EACs. By separating EAC cell lines according to the genetic cross background, for two of the genes (Phf5 and Met), we showed that the expression pattern differed significantly between different cross backgrounds, which clearly pinpoint the importance of using animal models as a complement to clinical studies in identification of cancer-related genes.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013
Keyword
Endometrial cancer, Genetic background, BDII rat model, SKY, Chromosomal abreations, Gene expression
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-7421 (URN)978-91-7668-913-4 (ISBN)
Public defence
2013-03-01, Insikten, Högskolan i Skövde, Skövde, 13:15 (Swedish)
Opponent
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Available from: 2013-03-18 Created: 2013-03-18 Last updated: 2014-03-27Bibliographically approved

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Falck, EvaKarlsson, SandraCarlsson, JessicaKlinga-Levan, Karin
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