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DNA methylation and expression of the folate transporting genes in colorectal cancer
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Department of Laboratory Medicine; Örebro University Hospital; Örebro, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

This study investigated the DNA methylation pattern and protein expression of the FOLR1, PCFT, and RFC1 genes in colorectal cancer (CRC) tissue. Our results showed statistically significant differences in the DNA methylated fraction of all three genes at several gene regions, we identified 3 differentially methylated CpG sites in the FOLR1 gene, 5 CpG sites in the PCFT gene, and 6 CpG sites in the RFC1 gene. We observed a pronounced expression of the FRα and RFC proteins in both the cancer and normal tissues, though the proteins were moderately expressed in cancer compared to the high expression in the paired healthy mucosa. The PCFT protein was undetectable or expressed very low in both tissues. Higher methylated fractions of the CpG sites 3-5 in the RFC1 gene were associated with a lower protein expression. When analyzing the association between DNA methylation and tumor characteristics (differentiation, location, primary tumor stage and lymph node involvement) we detected lower methylated fraction of specific CpG sites in the RFC1 gene in CRC located in the distal colon and rectum compared to the proximal colon. In the FOLR1 gene, we found CpG sites with a lower methylated fraction of colorectal cancers with the primary tumor stage 4 (pT4) compared to the pT2 and pT3 stages. Our results did not show association between the RFC and FRα protein expression and tumor stage, TNM classification or tumor location. In conclusion, these data suggest that there is a possible epigenetic regulation by DNA methylation of the RFC1 gene in the colorectal cancer.

Keyword [en]
CpG, T-DMR, reduced folate carrier, CRC, immunohistochemistry
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-35869OAI: oai:DiVA.org:oru-35869DiVA: diva2:736556
Available from: 2014-08-07 Created: 2014-08-07 Last updated: 2017-10-17Bibliographically approved
In thesis
1. DNA methylation in the placenta and in cancerwith special reference to folate transporting genes
Open this publication in new window or tab >>DNA methylation in the placenta and in cancerwith special reference to folate transporting genes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DNA methylation is an epigenetic mechanism that regulates the gene transcription. Folate is used in cellular synthesis of methyl groups, nucleic acids and amino acids. In complex diseases like cancer and neural tube defects (NTD), various genetic and epigenetic alterations can be found that disrupt the normal cell function. The main goals of this thesis were to analyze whether the genes responsible for the folate transport (FOLR1, PCFT, and RFC1) could be regulated by DNA methylation in placenta, blood leukocytes and colorectal cancer. We also addressed the genome-wide DNA methylation changes in colorectal cancer andcervical cancer.We found that changes in the methylated fraction of the RFC1 gene were dependent on the RFC1 80G>A polymorphism in placental specimens with NTDs and blood leukocytes from subjects with high homocysteine (Paper I). In colorectal cancer, the greatest difference in DNA methylation was observed in the RFC1 gene and was related to a lower protein expression (Paper II).In Paper III and IV we studied the DNA methylated fraction using a high-density array. Paper III was focused on genes in the DNA repair pathway and frequently mutated in colorectal cancer. We found that aberrant methylation in the DNA mismatch repair genes was not a frequent event in colorectal cancer and we identified five candidate biomarker genes in colorectal cancer, among them the GPC6 and DCLRE1C genes. In Paper IV, we found hypomethylation of genes involved in the immune system in cervical cancer specimens compared to healthy cervical scrapes and we identified twenty four candidate genes for further evaluation ofclinical value.In conclusion, the work of this thesis filled a relevant knowledge gap regarding the role of differential methylation of the folate transport genes in NTD and colorectal cancer. This thesis work also provided insights into the functional role of DNA methylation in cancer specific pathways and identified potential novel biomarker genes.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2014. 67 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 100
Keyword
DNA methylation, CRC, placenta, cervix, leukocytes, T-DMRs, folate, array, expression
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32599 (URN)978-91-7668-986-8 (ISBN)
Public defence
2014-01-31, Wilandersalen, Universitetssjukhuset, S. Grev Rosengatan, 703 62 Örebro, 09:15 (English)
Opponent
Supervisors
Available from: 2013-12-02 Created: 2013-12-02 Last updated: 2017-10-17Bibliographically approved

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Farkas, Sanja A.Hahn-Strömberg, VictoriaNilsson, Torbjörn K.
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