1. ¹Division of Functional Genomics, Jichi Medical School, Tochigi, Japan
2. ²Department of Surgery, Jichi Medical School, Tochigi, Japan
3. ³Division of Experimental Pathology, Mayo Clinic and Mayo Medical School, Rochester, MN, USA
4. ⁴CREST, Japan Science and Technology Agency, Saitama, Japan

Correspondence: Professor H Mano, Division of Functional Genomics, Jichi Medical School, 3311-1 Yakushiji, Kawachigun, Tochigi 329-0498, Japan. E-mail: hmano@jichi.ac.jp

Received 28 April 2005; Revised 7 July 2005; Accepted 13 July 2005; Published online 10 October 2005.

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.