Hypericin impedes M2 macrophage polarization and protects against Hepatocellular carcinoma

There has been increasing evidence that M2 polarization, which is essential for tumor growth, is present in most tumor-associated macrophages. Hypericin is the major component of the Traditional Chinese Medicine Hypericum perforatum. Hypericin exhibits antitumor activities, but its regulation on M2 macrophage polarization and the protective against Hepatocellular carcinoma (HCC) remains unknown.

IL-4 was used to induce bone marrow-derived macrophages (BMDMs) to differentiate into M2 macrophages, the effect of hypericin on M2 polarization of BMDMs was investigated, mRNA level of M2-related genes was determined using RT-qPCR and flow cytometry. Furthermore, the effect of culture medium of M2 macrophage (M2-CM) pretreated with hypericin or not on the proliferation, migration, and invasion of Hepa1-6 cells was studied. To investigate the mechanism, the PI3K/AKT signaling pathway, which is critical in macrophage polarization was tested. A mouse model of HCC was established by subcutaneous implantation of H22 cells, the impact of Hyp on tumor growth and M2 macrophage polarization in tumor tissues was identified.

In the present study, we found that Hyp significantly inhibited M2 polarization of macrophages, as indicated by decreased expression of CD206 and M2-related markers, moreover, Hyp suppressed the M2-CM-induced proliferation, invasion and migration of Hepa1-6 cells. Hyp manifested an inhibitory effect on the PI3K/AKT signaling pathway during the differentiation of M2 macrophages. In vivo experiments showed that Hyp greatly suppressed tumor growth and reduced M2 macrophage polarization in tumor tissues.

Hyp impedes the growth, proliferation, invasion and migration of HCC by inhibiting M2 macrophages polarization via the PI3K/AKT signaling pathway, our data demonstrate that hypericin may be a promising candidate for HCC treatment.