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.
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Acknowledgements
We thank M Toyota and SN Thibodeau for critical reading of the manuscript and helpful suggestions. This study was supported in part by a grant for Third-Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor, and Welfare of Japan, and by a grant for ‘High-Tech Research Center’ Project for Private Universities: Matching Fund Subsidy (2002–2006) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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Koinuma, K., Yamashita, Y., Liu, W. et al. Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability. Oncogene 25, 139–146 (2006). https://doi.org/10.1038/sj.onc.1209009
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DOI: https://doi.org/10.1038/sj.onc.1209009
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