Low expression of reduced folate carrier-1 and folylpolyglutamate synthase correlates with lack of a deleted in colorectal carcinoma mRNA splice variant in normal-appearing mucosa of colorectal carcinoma patients
Journal article, 2005
BACKGROUND: Cellular folate deficiency leads to DNA strand breaks, mutations, and aberrant methylation and might be a risk factor for colorectal cancer (CRC). The putative tumor suppressor gene deleted in colorectal carcinoma (DCC) is one of several genes the expression of which seems to be affected by the folate concentration at the tissue level. Decreased expression of DCC may be caused by LOH or hypermethylation, i.e. by events that might be linked to folate deficiency. The purpose of this study was to analyze if the folate level and the gene expression levels of reduced folate carrier (RFC-1) and folylpolyglutamate synthase (FPGS) had impact on the expression of DCC splice variants. METHODS: Quantification of RFC-1 and FPGS expression in mucosa of 53 CRC patients was performed using real-time PCR whereas DCC splicing variants were detected by automated capillary gel electrophoresis. Total reduced folate concentration was measured with the FdUMP-binding assay (n = 22). RESULTS: Significantly higher expression levels of RFC-1 (p = 0.026) and FPGS (p = 0.05) were found in mucosa expressing the splice variant DCC342 compared to mucosa that did not. Furthermore, multivariate analysis showed that RFC-1 and FPGS (r = 0.49, p = 0.01) as well as folate and RFC-1 (r = 0.56, p = 0.023) were correlated only in mucosa expressing DCC342. CONCLUSIONS: In conclusion, the present study points to a potential influence of folates in regulating DCC expression at multiple levels involving post-transcriptional pathways. The results may provide a basis for a detailed investigation of molecular mechanisms involved in folate regulation of DCC expression.
Neoplasm/*genetics
RNA
Molecular Sequence Data
Middle Aged
Intestinal Mucosa/*chemistry
Multivariate Analysis
Aged
Male
Female
Colorectal Neoplasms/chemistry/*genetics/pathology
Sweden
Amino Acid Sequence
Genes
Aged
Peptide Synthases/analysis/*genetics
Neoplastic
Reverse Transcriptase Polymerase Chain Reaction
Gene Expression Regulation
Adenocarcinoma/chemistry/*genetics/pathology
80 and over
*Alternative Splicing
Adult
Membrane Transport Proteins/analysis/*genetics
DCC/genetics
Humans
Folic Acid Deficiency/genetics
Author
Yvonne Wettergren
Elisabeth Odin
University of Gothenburg
Staffan Nilsson
University of Gothenburg
Chalmers, Mathematical Sciences, Mathematical Statistics
Roger Willen
Göran Carlsson
Bengt Gustavsson
University of Gothenburg
Cancer Detection and Prevention
0361-090X (ISSN) 1525-1500 (eISSN)
Vol. 29 4 348-55Subject Categories
Surgery
DOI
10.1016/j.cdp.2005.06.006
PubMed
16122883