Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability.
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.
Koinuma
K
K
Division of Functional Genomics, Jichi Medical School, Tochigi, Japan.
Yamashita
Y
Y
Liu
W
W
Hatanaka
H
H
Kurashina
K
K
Wada
T
T
Takada
S
S
Kaneda
R
R
Choi
Y L
YL
Fujiwara
S-I
SI
Miyakura
Y
Y
Nagai
H
H
Mano
H
H
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
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