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

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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.