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Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability

K Koinuma1, Y Yamashita, W Liu

  • 1Division of Functional Genomics, Jichi Medical School, Tochigi, Japan.

Oncogene
|October 26, 2005
PubMed

Insights

Microsatellite instability (MSI) in colorectal cancer (CRC) is linked to distinct gene expression changes. Epigenetic silencing of the AXIN2 gene specifically occurs in MSI+ CRCs, impacting tumor formation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Microsatellite instability (MSI) arises from mutations in mismatch repair genes (e.g., MLH1, MSH2) in a subset of colorectal carcinomas (CRCs).
  • The specific genes driving tumor formation in MSI-positive (MSI+) CRCs remain largely uncharacterized.

Purpose of the Study:

  • To identify and characterize MSI-dependent gene expression alterations in colorectal cancer.
  • To investigate the role of specific genes, such as AXIN2, in the development of MSI+ CRCs.

Main Methods:

  • Transcriptome comparison of fresh colorectal cancer specimens (n=10 MSI+ vs. n=10 MSI-) using high-density oligonucleotide microarrays (>44,000 probe sets).
  • Correspondence analysis to identify MSI-associated genes.
  • Analysis of AXIN2 promoter methylation and expression.
  • Functional studies involving AXIN2 re-expression in an MSI+ CRC cell line using 5'-azacytidine or cDNA transfection.

Main Results:

  • Transcriptomes of MSI+ and MSI- CRCs are distinctly different, as revealed by correspondence analysis.
  • AXIN2, a WNT signaling pathway component, was found to be epigenetically silenced (via promoter methylation) specifically in MSI+ CRCs.
  • Forced expression of AXIN2 in an MSI+ CRC cell line induced rapid cell death.

Conclusions:

  • Epigenetic silencing of AXIN2 is a specific event associated with carcinogenesis in MSI+ colorectal cancer.
  • AXIN2 may play a critical role in tumor suppression within the context of MSI+ CRCs.

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