Abstract
Mutation or epigenetic silencing of mismatch repair genes, such as MLH1 and MSH2, results in microsatellite instability (MSI) in the genome of a subset of colorectal carcinomas (CRCs). However, little is yet known of genes that directly contribute to tumor formation in such cancers. To characterize MSI-dependent changes in gene expression, we have now compared transcriptomes between fresh CRC specimens positive or negative for MSI (n=10 for each) with the use of high-density oligonucleotide microarrays harboring >44,000 probe sets. Correspondence analysis of the expression patterns of isolated MSI-associated genes revealed that the transcriptome of MSI+ CRCs is clearly distinct from that of MSI- CRCs. Such MSI-associated genes included that for AXIN2, an important component of the WNT signaling pathway. AXIN2 was silenced, apparently as a result of extensive methylation of its promoter region, specifically in MSI+ CRC specimens. Forced expression of AXIN2, either by treatment with 5'-azacytidine or by transfection with AXIN2 cDNA, resulted in rapid cell death in an MSI+ CRC cell line. These data indicate that epigenetic silencing of AXIN2 is specifically associated with carcinogenesis in MSI+ CRCs.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Adult
-
Aged
-
Aged, 80 and over
-
Axin Protein
-
Azacitidine / pharmacology
-
Benzothiazoles
-
Carrier Proteins / metabolism
-
Cell Death
-
Cell Line, Tumor
-
Cell Proliferation
-
Cluster Analysis
-
Colorectal Neoplasms / genetics*
-
Colorectal Neoplasms / metabolism*
-
CpG Islands
-
Cytoskeletal Proteins / genetics*
-
Cytoskeletal Proteins / metabolism
-
DNA Methylation
-
DNA Repair
-
DNA, Complementary / metabolism
-
Diamines
-
Epigenesis, Genetic*
-
Female
-
Gene Silencing*
-
Humans
-
Male
-
Microsatellite Repeats*
-
Middle Aged
-
MutL Protein Homolog 1
-
MutS Homolog 2 Protein / metabolism
-
Nuclear Proteins / metabolism
-
Oligonucleotide Array Sequence Analysis
-
Organic Chemicals / pharmacology
-
Quinolines
-
RNA, Messenger / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Time Factors
-
Transfection
-
Up-Regulation
Substances
-
AXIN2 protein, human
-
Adaptor Proteins, Signal Transducing
-
Axin Protein
-
Benzothiazoles
-
Carrier Proteins
-
Cytoskeletal Proteins
-
DNA, Complementary
-
Diamines
-
MLH1 protein, human
-
Nuclear Proteins
-
Organic Chemicals
-
Quinolines
-
RNA, Messenger
-
SYBR Green I
-
MutL Protein Homolog 1
-
MutS Homolog 2 Protein
-
Azacitidine