Targeting tumor microenvironment: Metformin suppresses IL-22 induced hepatocellular carcinoma by upregulating Hippo signaling pathway

BackgroundEpidemiological studies have shown direct associations between type 2 diabetes and the risk of cancers. Accumulating evidence indicates that metformin is profoundly implicated in preventing tumor development. However, the exact mechanism underlying the anti-tumor effects of metformin in hepatocellular carcinoma (HCC) is still not clear. MethodsIn this study, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and interleukin-22 (IL-22)-associated carcinogenesis in vitro.ResultsWe found that metformin significantly suppressed the incidence and tumor burden of HCC in the diethyl-nitrosamine (DEN)-induced HCC mouse model. As expected, expression of IL-22, an important factor involved in HCC progression, was markedly reduced by metformin. Treatment of HCC cells with metformin inhibited IL-22 induced cell proliferation, migration and invasion, and promoted cell apoptosis. Furthermore, ectopic expression of IL-22 makes HCC more aggressive whereas metformin largely compromised it in vitro and in vivo. Mechanistically, the whole transcriptome analysis and functional analysis revealed that Hippo signaling pathway was involved in the anti-tumor ability of metformin. Consistent with this, metformin directly activated Mst1/2, phosphorylated YAP1 in vitro. After blocking Hippo pathway by XMU-MP-1, the inhibitor of MST1/2, the inhibitory effects by metformin were dramatically attenuated as shown by in vitro study.ConclusionsCollectively, our findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate IL-22 mediated HCC progression and provide new insights into its tumor-suppressive roles.