Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability

Oncogene. 2006 Jan 5;25(1):139-46. doi: 10.1038/sj.onc.1209009.

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
  • 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
  • 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
  • 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
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DNA, Complementary
  • MLH1 protein, human
  • Nuclear Proteins
  • Organic Chemicals
  • RNA, Messenger
  • SYBR Green I
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Azacitidine