IL-35 promotes EMT through STAT3 activation and induces MET by promoting M2 macrophage polarization in HCC

The tumor microenvironment and interplay with cancer cells could promote tumor growth and metastasis. Here we report that polarization state of macrophages could affect epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial transition (MET). IL-35 level secreted by M1 macrophage was significantly higher than M2 macrophage and it facilitated EMT process through activation of STAT3 in hepatocellular carcinoma cells. Interestingly, IL-35 could not directly promote MET, but it could indirectly induce MET of HCC cells through M2 macrophage polarization. These results indicated the level of IL-35 in tumor microenvironment may fluctuate at different stages of oncogenesis to regulate epithelial plasticity of HCC and provide potential therapeutic targets for tumor metastasis.