Koinuma K, Yamashita Y, Liu W, Hatanaka H, Kurashina K, Wada T, Takada S, Kaneda R, Choi Y L, Fujiwara S-I, Miyakura Y, Nagai H, Mano H
Division of Functional Genomics, Jichi Medical School, Tochigi, Japan.
Oncogene. 2006 Jan 5;25(1):139-46. doi: 10.1038/sj.onc.1209009.
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.
错配修复基因（如MLH1和MSH2）的突变或表观遗传沉默会导致一部分结直肠癌（CRC）基因组中的微卫星不稳定性（MSI）。然而，对于此类癌症中直接促成肿瘤形成的基因，我们目前了解甚少。为了表征MSI依赖性的基因表达变化，我们现在使用包含超过44,000个探针组的高密度寡核苷酸微阵列，比较了MSI阳性或阴性的新鲜CRC标本（每组n = 10）之间的转录组。对分离出的MSI相关基因的表达模式进行对应分析表明，MSI + CRCs的转录组与MSI - CRCs的转录组明显不同。此类MSI相关基因包括WNT信号通路的重要组成部分AXIN2的基因。AXIN2被沉默，显然是其启动子区域广泛甲基化的结果，特别是在MSI + CRC标本中。通过用5'-氮杂胞苷处理或用AXIN2 cDNA转染来强制表达AXIN2，会导致MSI + CRC细胞系中的细胞迅速死亡。这些数据表明，AXIN2的表观遗传沉默与MSI + CRCs的致癌作用特别相关。
