Analysis of roles of alterations in non-coding region of genes in carcinogenesis with microsatellite instability

我们已经确定了癌症相关基因的表达调控的微卫星长度在非编码区。我们还揭示了微卫星长度的改变对这些基因的表达在体外和体内实验的影响。这些基因的突变频率在MSI阳性的胃肠道癌组织和细胞系中显示。在特定的基因中，开发了几个具有不同微卫星长度的亚克隆。在这些亚克隆和MSI阳性的胃肠道肿瘤组织和细胞系中，微卫星长度与基因表达相关，其中位于5 '-UTR的靶基因在MSI阳性的肿瘤中表达下调。MSI可能是导致含有5 '-UTR微卫星的基因转录水平降低的原因。5 '-UTR的改变可降低转录效率。因此，这似乎是肿瘤抑制基因失活的机制之一。另一方面，在MSI阳性癌症中，其单核苷酸重复序列位于3 '-UTR的靶基因的表达通常上调。此外，在癌症中重复长度通常缩短。这似乎是致癌基因激活的潜在机制之一。我们还发现poly（U）-tract的长度可以影响RNA的稳定性和加工翻译效率，这些结果提示肿瘤相关基因非编码区微卫星长度的改变在MSI阳性胃肠道肿瘤的发生发展中起重要作用。

We have identified cancer-related genes of which expressions are regulated by microsatellite length in non-coding region. We have also revealed the effects of microsatellite length alterations on the expression of these genes by in vitro and in vivo experiments. Frequency of mutations of these genes was shown in MSI-positive gastrointestinal cancer tissues and cell lines. Several subclones with different microsatellite length in particular genes were developed. Correlation of microsatellite length with gene expression was shown in these subclones and MSI-positive gastrointestinal cancer tissues and cell lines.The expression of target genes of which mononucleotide repeats were located in 5'-UTR was often downregulated in MSI-positive cancers. MSI could be responsible for the decreased transcript levels of genes containing 5'-UTR microsatellites. Alterations in the 5'-UTR could diminish transcription efficiency. Thus, this appears one of the mechanisms underlying the inactivation of tumor suppressor genes. On the other hand, the expression of target genes of which mononucleotide repeats were located in 3'-UTR was often upregulated in MSI-positive cancers. Moreover, the repeat length was often shortened in cancer. This seems one of the mechanisms underlying activation of oncogenes. We have also revealed that poly(U)-tract length could affect RNA stability and processing and translation efficiency.These results suggest that microsatellite length alterations in non-coding region of cancer-related genes play an important role in the development and progression of MSI-positive gastrointestinal cancers.