| セッション情報 |
The 2nd JSGE International Topic Conference
2）Animal Models of Hepatocellular Carcinoma
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| タイトル |
IT2-2：Functional Impairment of microRNAs by Chronic Inflammation is a Cause of Inflammation-associated Tumorigenesis in Mice
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| 演者 |
Otsuka Motoyuki（Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan） |
| 共同演者 |
Yoshikawa Takeshi（Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan）, Koike Kazuhiko（Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan） |
| 抄録 |
Background：A widespread downregulation of microRNAs is commonly observed in human cancers and is involved in cellular transformation. Because we previously reported that microRNA functions are inhibited under inflammatory cytokines in vitro, we hypothesized that chronic inflammation in vivo may also cause chronic functional impairment of microRNAs, which mimics a global reduction of microRNA levels, resulting in a causal role in inflammation-associated tumorigenesis.
Methods ＆ Results：1）We constructed GFP-based reporter mice with target sequences of microRNAs in its 3’UTR, to monitor the changes of microRNA functions. The expression levels of GFP were significantly increased during DSS-induced colitis, suggesting that microRNA functions were impaired during the chronic inflammation. 2）To determine the consequences of global functional impairment of microRNAs, we examined Dicer-deficient mice, which have globally low levels of microRNA expression and may mimic the functional impairment of global microRNAs. As expected, Dicer-deficient mice were more liable to colitis-associated tumors. 3）We treated mice with a ROCK inhibitor, which was found as a potentiator of miRNA function from a drug-library screen. ROCK inhibition efficiently prevented colitis-associated tumorigenesis, suggesting that potentiation of miRNA-function can be a preventive method against inflammation-associated tumors. 4）To expand these findings into the liver, mouse HCC models, which develop inflammation-associated HCCs, are currently under investigation.
Conclusion：We propose that the attenuation of global microRNA functions by chronic inflammation is the cause of inflammation-associated tumorigenesis, which may be prevented by the potentiation of miRNA-function. |
| 索引用語 |
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