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Functional screening of novel regulatory factors of cancer development
In many patients that suffer from solid cancers, the presence or absence of unresectable metastases profoundly affects their prognosis. Understanding mechanisms by which cancer cells with metastatic ability emerge during carcinogenesis and eventually form metastatic foci in distant organs is crucial in eradicating metastasis.
In order to recapitulate liver metastasis of colon cancer, we developed an experimental model in which cancer metastasis was generated with high efficiency in highly immuno-compromised NOG mice. This metastasis model was used to functionally isolate regulatory factors involved in liver metastasis of colon cancer cells. First we looked for miRNAs that can inhibit liver metastasis of colon cancer cells by applying a systematic screening approach (Izumiya et al., Carcinogenesis, 2010). Through the dropout screening of a miRNA library after its introduction of HCT116 colon cancer cells, miR-493 was isolated as a metastasis-inhibitory miRNA (Okamoto et al., EMBO J. 2012). High levels of miR-493 in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. Subsequently IGF1R and MKK7 was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects (Sakai et al., Cancer Sci, 2014).
We also performed similar functional screening in collaboration with Dr. Satoshi Inoue (Tokyo Metropolitan Institute of Gerontology), and identified novel regulators of cancer progression (Maruyama et al., PLoS One, 2014; Ujihara et al., Sci. Rep, 2015; Miyazaki et al., J. Clin. Med, 2015).
In addition, we are isolating genes that regulate chemoresistance and distant metastasis of colon and ovarian cancer by using functional screening methods after lentiviral infection of shRNA/sgRNA libraries.