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Cell Death Dis. 2018 May 1;9(5):489. doi: 10.1038/s41419-018-0477-1.

Repression of let-7a cluster prevents adhesion of colorectal cancer cells by enforcing a mesenchymal phenotype in presence of liver inflammation.

Author information

1
Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
2
Department of General Surgery, People's Liberation Army Nanjing General Hospital, Nanjing, 210002, China.
3
Department of Hepatobiliary Pancreatic and Spleen Surgery, Xuzhou Central Hospital, Xuzhou, 221000, China.
4
Research Center of Developmental Biology, Second Military Medical University, Shanghai, 200433, China. wangyuesmmu@163.com.
5
Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China. jmyang@smmu.edu.cn.

Abstract

The liver is the most common site of metastasis in patients with colorectal cancer, and colorectal cancer liver metastasis (CRLM) is associated with poor rates of survival. However, CRLM occurs infrequently in livers exhibiting signs of hepatitis or cirrhosis, suggesting a role for inflammation in attenuating CRLM. The molecular mechanisms driving this phenomenon remain unclear. The aim of this study was to confirm the mechanism by which liver inflammation inhibits CRLM. We used BALB/c animal models of inflammatory liver diseases to confirm that liver inflammation inhibits CRLM, and then elucidated the molecular mechanisms governing that process. Out data showed that liver inflammation induces IFN-γ expression, which then downregulates expression of the let-7a cluster through IRF-1 in colorectal cancer cells. Finally, we showed that modulation of let-7a expression regulated the epithelial-mesenchymal transition in colorectal cancer cell lines, and inhibited their capacity to metastasize in vivo. Cumulatively, we clarified the critical role played by the IFN-γ/IRF-1/let-7a cluster/EMT pathway in regulating the spread of circulating colorectal cancer cells to the liver, and highlighted the critical role that the hepatitis microenvironment plays in modulating that process.

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