title: Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability.
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.
authors.affiliation: Division of Functional Genomics, Jichi Medical School, Tochigi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Koinuma
authors.forename: Y
authors.initials: Y
authors.lastname: Yamashita
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Hatanaka
authors.forename: K
authors.initials: K
authors.lastname: Kurashina
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: S
authors.initials: S
authors.lastname: Takada
authors.forename: R
authors.initials: R
authors.lastname: Kaneda
authors.forename: Y L
authors.initials: YL
authors.lastname: Choi
authors.forename: S-I
authors.initials: SI
authors.lastname: Fujiwara
authors.forename: Y
authors.initials: Y
authors.lastname: Miyakura
authors.forename: H
authors.initials: H
authors.lastname: Nagai
authors.forename: H
authors.initials: H
authors.lastname: Mano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060466:Axin Protein; D001374:Azacitidine / Q000494:pharmacology; D052160:Benzothiazoles; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004260:DNA Repair; D018076:DNA, Complementary / Q000378:metabolism; D003959:Diamines; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009930:Organic Chemicals / Q000494:pharmacology; D011804:Quinolines; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C491761:AXIN2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D052160:Benzothiazoles; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D003959:Diamines; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D009930:Organic Chemicals; D011804:Quinolines; D012333:RNA, Messenger; C098022:SYBR Green I; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D001374:Azacitidine