Department of Special Treatment and Liver Transplantation, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, China.
Department of General Surgery, People's Liberation Army Nanjing General Hospital, Nanjing, 210002, China.
Cell Death Dis. 2018 May 1;9(5):489. doi: 10.1038/s41419-018-0477-1.
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.
肝脏是结直肠癌患者最常见的转移部位，结直肠癌肝转移（CRLM）与生存率低有关。然而，在有肝炎或肝硬化迹象的肝脏中，CRLM 很少发生，这表明炎症在减轻 CRLM 中起作用。驱动这种现象的分子机制仍不清楚。本研究旨在证实肝炎症抑制 CRLM 的机制。我们使用 BALB/c 动物炎症性肝病模型来证实肝炎症抑制 CRLM，然后阐明了控制该过程的分子机制。我们的数据表明，肝炎症诱导 IFN-γ 的表达，然后通过 IRF-1 在结直肠癌细胞中下调 let-7a 簇的表达。最后，我们表明，调节 let-7a 的表达可调节结直肠癌细胞系中的上皮-间充质转化，并抑制其在体内转移的能力。总的来说，我们阐明了 IFN-γ/IRF-1/let-7a 簇/EMT 途径在调节循环结直肠癌细胞向肝脏扩散中的关键作用，并强调了肝炎微环境在调节该过程中的关键作用。
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